CD2
T-cell surface antigen CD2 precursor (Erythrocyte receptor) (LFA-2) (LFA-3 receptor) (Rosette receptor) (T-cell surface antigen T11/Leu-5) (CD2 antigen) [SRBC]
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Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.
MeSH Terms
- CD57 Antigens
- Coinfection
- Cytomegalovirus Infections
- HIV Infections
- Hepatitis A Virus Cellular Receptor 2
- Hepatitis C
- Humans
- Killer Cells, Natural
- NK Cell Lectin-Like Receptor Subfamily C
Keywords
- aging
- cancer
- checkpoint blockade
- chronic infection
- exhaustion
- maturation
- natural killer cells
- senescence
The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts. In the AA population, we identified nine novel regions (KLF4-ACTL7B, RAPGEF2-FSTL5, TCF4-LOC100505474, PCDH10, KIAA1751, MYO5B, MIR320B1-CD2, NR5A2-LINC00862, SALL1-C16orf97) that were associated with the sense of smell (P < 5 × 10 ). Many of these regions have been previously linked to neuropsychiatric (schizophrenia or epilepsy) or neurodegenerative (Parkinson's or Alzheimer's disease) diseases associated with a decreased sense of smell. In the EA population, we identified two novel loci in or near RASGRP1 and ANXA2P3 associated with sense of smell. In conclusion, this study identified several ancestry-specific loci that are associated with the sense of smell in older adults. While these findings need independent confirmation, they may lead to novel insights into the biology of the sense of smell in older adults and its relationships to neuropsychological and neurodegenerative diseases.
MeSH Terms
- African Americans
- Aged
- Aging
- European Continental Ancestry Group
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genotype
- Humans
- Male
- Polymorphism, Single Nucleotide
- Risk
- Smell
- United States
Keywords
- African-American
- GWAS
- The sense of smell
The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3ε, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease.
MeSH Terms
- Age Factors
- Animals
- Cell Proliferation
- Disease Progression
- Humans
- Mice
- Neoplasms
- Signal Transduction
- Spleen
- Tumor Microenvironment
Keywords
- CD2
- CD3e
- Gerotarget
- aging and cancer
- tumor microenvironment
- tumor progression
Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that CD2, CD3e, CD68, CD45, TNF-α, IL6, CCL2, ATF3 and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in CCL2, and IL6, and elevated ATF3 mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased ATF3); whereas, levels of GFAP protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain.
MeSH Terms
- Age Factors
- Aging
- Animals
- Antigens, CD
- Cytokines
- Ganglia, Spinal
- Male
- Microglia
- Neuralgia
- Nociception
- Rats
- Satellite Cells, Perineuronal
- Sciatic Neuropathy
- Spinal Cord
Depression is one of the most frequently missed diagnoses in elderly people, with obvious negative effects on quality of life. Various studies have shown that long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) may be useful in its management. Our objective was to evaluate whether a supplement containing n-3 PUFA improves depressive symptoms in depressed elderly patients, and whether the blood fatty acid pattern is correlated with these changes. The severity of depressive symptoms according to the Geriatric Depression Scale (GDS), blood fatty acid composition and erythrocyte phospholipids were analyzed in 46 depressed females aged 66-95y, diagnosed with depression according to DSMIV, within the context of a randomized, double-blind, placebo-controlled trial. 22 depressed females were included in the intervention group (2.5 g/day of n-3 PUFA for 8 weeks), and 24 in the placebo group. We also measured immunological parameters (CD2, CD3, CD4, CD8, CD16, CD19 and cytokines (IL-5, IL-15). The mean GDS score and AA/EPA ratio, in whole blood and RBC membrane phospholipids, were significantly lower after 2 months supplementation with n-3 PUFA. A significant correlation between the amelioration of GDS and the AA/EPA ratio with some immunological parameters, such as CD2, CD19, CD4, CD16 and the ratio CD4/CD8, was also found. Nevertheless, omega-3 supplementation did not significantly improve the studied immunological functions. n-3 PUFA supplementation ameliorates symptoms in elderly depression. The n-3 PUFA status may be monitored by means of the determination of whole blood AA/EPA ratio.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Antidepressive Agents
- Antigens, CD
- Arachidonic Acid
- Cytokines
- Depression
- Diagnostic and Statistical Manual of Mental Disorders
- Dietary Supplements
- Double-Blind Method
- Eicosapentaenoic Acid
- Erythrocyte Membrane
- Fatty Acids, Omega-3
- Female
- Geriatric Assessment
- Humans
- Lymphocyte Subsets
- Phospholipids
- Severity of Illness Index
Human natural killer (NK) cells subsets are phenotypically characterized by their lack of CD3 and low/high expression of CD56. This study revealed an age-associated increase in the ratio of CD3(-)CD56(dim) to CD3(-)CD56(bright) NK cells, whereas distinct expression patterns of CD2, CD16, CD57, and the C-type lectin family members killer cell lectin-like receptor -D1 (CD94) and -G1 (KLRG1), were noted on both these NK and the CD3( )CD56( ) T cell subsets; moreover, CD94 and KLRG1 expression were significantly reduced with age. Although the proportion of CD3(-)CD56(bright) NK cells vs CD3(-)CD56(dim) cells decreased with age, the percentage of CD3(-)CD56(bright) cells expressing IFN-gamma after activation significantly increased, potentially representing compensatory augmentation of cytokine production to maintain the important immunoregulatory role of these cells in older individuals. Collectively, these results highlight new evidence for a continuum of change during immunologic aging and present unique data for variation of NK cell subsets with human aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- CD3 Complex
- CD56 Antigen
- Cell Count
- Humans
- Immunophenotyping
- Interferon-gamma
- Interleukin-15
- Killer Cells, Natural
- Lectins, C-Type
- Leukocytes, Mononuclear
- Lymphocyte Subsets
- Lysosomal-Associated Membrane Protein 1
- Middle Aged
- Receptors, Immunologic
- Trans-Activators
- Young Adult
Assessment of lymphocyte subsets is an effective method for characterizing disorders such as leukemia, lymphomas, autoimmune and infectious diseases. In order to clinically interpret these parameters, normal reference values should be set, estimating age- and gender-related variations. This research aimed to: (1) characterize lymphocyte subpopulations in Andalusian horse, and (2) evaluate age and gender-related variations of lymphocyte subsets. Jugular blood samples were obtained from 159 animals, 77 males and 82 females, belonging to four age groups-1: 1-2 years (N=39; 21 males and 18 females), 2: 2-3 years (N=38; 16 males and 22 females), 3: 3-4 years (N=41; 19 males and 22 females) and 4: 4-7 years (N=41; 21 males and 20 females). T lymphocytes subsets were quantified by flow cytometry with monoclonal antibodies specific for CD2, CD4 and CD8 cell markers. B and NK cell counts were estimated by using a mathematical formula. No variations were found in T, B lymphocytes and NK cells between males and females. Animals of group 1 and 2 had a higher number of CD2, T, CD4 , CD8 , B lymphocytes and NK cells than animals of groups 3 and 4. The percentage of CD2 in group 1 was significantly lower than in group 4. The percentage of T and CD4 lymphocytes in the group 1 were significantly higher than groups 2 and 3, respectively. Whereas the percentage of B cells calculated by flow cytometry was significantly lower in group 2 compared to group 4, the percentage of B cells calculated by a mathematical formula was higher in group 1. NK cells percentage was significantly lower in group 3 and 4 than in younger animals. In conclusion, in Andalusian horse, gender does not influence absolute numbers and percentages of T, B and NK. There is an age-related decline in absolute number of CD2, T, CD4 and CD8 lymphocytes, B lymphocytes and NK cells, with increasing percentage of CD2, T, CD4 and B lymphocytes, and a decrease in NK with no differences in CD4/CD8 ratio. The decline of lymphocyte population numbers with age is a natural process in many animal species, and could be the origin for immune dysfunction observed in geriatric individuals.
MeSH Terms
- Age Factors
- Aging
- Animals
- B-Lymphocyte Subsets
- CD4-CD8 Ratio
- Female
- Flow Cytometry
- Horses
- Immunophenotyping
- Killer Cells, Natural
- Lymphocyte Subsets
- Male
- Sex Characteristics
- Spain
- T-Lymphocyte Subsets
Gata transcription factors are critical regulators of proliferation and differentiation implicated in various human cancers, but specific genes activated by Gata proteins remain to be identified. We previously reported that enforced expression of Gata3 during T cell development in CD2-Gata3 transgenic mice induced CD4( )CD8( ) double-positive (DP) T cell lymphoma. Here, we show that the presence of the DO11.10 T-cell receptor transgene, which directs DP cells towards the CD4 lineage, resulted in enhanced lymphoma development and a dramatic increase in thymocyte cell size in CD2-Gata3 transgenic mice. CD2-Gata3 DP cells expressed high levels of the proto-oncogene c-Myc but the Notch1 signaling pathway, which is known to induce c-Myc, was not activated. Gene expression profiling showed that in CD2-Gata3 lymphoma cells transcription of c-Myc and its target genes was further increased. A substantial fraction of CD2-Gata3 lymphomas had trisomy of chromosome 15, leading to an increased c-Myc gene dose. Interestingly, most lymphomas showed high expression of the Notch targets Deltex1 and Hes1, often due to activating Notch1 PEST domain mutations. Therefore, we conclude that enforced Gata3 expression converts DP thymocytes into a pre-malignant state, characterized by high c-Myc expression, whereby subsequent induction of Notch1 signaling cooperates to establish malignant transformation. The finding that Gata3 regulates c-Myc expression levels, in a direct or indirect fashion, may explain the parallel phenotypes of mice with overexpression or deficiency of either of the two transcription factors.
MeSH Terms
- Aging
- Animals
- CD2 Antigens
- CD4-Positive T-Lymphocytes
- Cell Lineage
- Cell Size
- Cell Transformation, Neoplastic
- Chromosome Aberrations
- Chromosomes, Mammalian
- Exons
- Flow Cytometry
- GATA3 Transcription Factor
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Lymphoma
- Mice
- Mice, Transgenic
- Mutation
- Proto-Oncogene Proteins c-myc
- Receptor, Notch1
- Selection, Genetic
- T-Lymphocytes
We used transgenic mice to investigate the effect of IL-2 stimulation on T lymphocyte functions of GILZ-overexpressing splenic T cells. When compared to their controls, T cells from transgenic mice underwent normal activation after stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies, as evaluated by CD25 expression, CD2 up-regulation and proliferation. IL-10, IL-13 and IFN-gamma increased more consistently in CD3/CD28-triggered TG compared to WT splenic CD4( )cells. Analysis of the CD4( )and CD8( )T cells demonstrated a decreased CD4( )/CD8( )T-cell ratio (1:1 instead of 1:2) in response to IL-2 stimulation, possibly due to an unresponsiveness of IL-2 receptor beta and/or gamma chains. Finally, the total number of T cells was significantly increased in aged mice and this was due to the augmentation of CD4( )T cells. These results support the hypothesis that GILZ regulates, at least in part, peripheral T-cell functions by influencing their responsiveness to IL-2.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytokines
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Interleukin-2
- Lymphocyte Activation
- Mice
- Mice, Transgenic
- Spleen
- Transcription Factors
The aim of this study was to investigate the distribution of immune cells in the endometrium of anoestrous female pigs, five sows in anoestrus by lactation and five pre-pubertal gilts (Swedish Landrace x Swedish Yorkshire). Uterine samples, taken immediately after slaughter, were fixed, embedded in plastic resin and stained with toluidine blue or cryo fixed and stored in a freezer at -70 degrees C until analysed by immunohistochemistry with an avidin-biotin peroxidase method. Immune cells in the surface (luminal) and the glandular epithelium as well as the subepithelial and the glandular connective tissue layers were counted using light microscopy. In the surface (luminal) and the glandular epithelia of gilts and sows, lymphocytes were the predominant immune cells found. There were no significant differences between gilts and sows. Macrophages were detected in the glandular epithelium of sows but not in gilts. In the subepithelial and the glandular connective tissue layers of both gilts and sows, lymphocytes were also the most common immune cells found. The numbers of lymphocytes and macrophages were significantly higher in the sows than in the gilts (p <or= 0.05) in both the layers of connective tissue. Numbers of plasma cells, mast cells, eosinophils and neutrophils in the connective tissue were low and not significantly different between sows and gilts. In both the surface (luminal) epithelium and the subepithelial connective tissue, higher numbers of CD2 than CD3 positive cells were found (p <or= 0.01). The numbers of CD2 positive cells in both epithelium and connective tissue and the number of CD3 positive cells in the epithelium were significantly higher in the sows than the gilts (p <or= 0.05). A few CD79 positive cells were found in the subepithelial connective tissue and none in the epithelia. A few CD14 and SWC3 positive cells were found in the epithelia. The numbers of CD14, SWC3 and MHC class II positive cells were significantly higher in the sows than in the gilts (p <or= 0.05) in the subepithelial connective tissue. In conclusion, the distribution of immune cells in the endometrium of anoestrous female pigs was affected by experienced pregnancy and parturition. In sows with lactation-induced anoestrus, there was a markedly higher cell infiltration (lymphocytes and macrophages) than in the pre-pubertal gilts. In pre-pubertal gilts, lymphocytes dominated, which indicates a role in the maturation of the endometrium.
MeSH Terms
- Aging
- Anestrus
- Animals
- Endometrium
- Female
- Immunohistochemistry
- Lactation
- Lymphocyte Subsets
- Lymphocytes
- Macrophages
- Sexual Maturation
- Swine
NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in beta selection checkpoint enforcement. At 5-8 wk of age, even in the absence of TCRbeta expression, CD4 and CD4 CD8 blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NODxB6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the beta selection program. They mimic normal beta selection by up-regulating germline TCR-Calpha transcripts, CD2, and Bcl-xL and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7Ralpha. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCRbeta rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.
MeSH Terms
- Aging
- Animals
- CD2 Antigens
- CD4 Antigens
- Cell Cycle
- Cell Differentiation
- Cell Division
- Gene Expression Regulation
- Genes, RAG-1
- Genes, Recessive
- Genes, T-Cell Receptor alpha
- Lymphopenia
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Mice, Transgenic
- Proto-Oncogene Proteins c-bcl-2
- Proto-Oncogene Proteins c-kit
- Receptors, Interleukin-7
- T-Lymphocyte Subsets
- Thymus Gland
- Transcription, Genetic
- Up-Regulation
- bcl-X Protein
We previously developed a transgenic mouse line into which a rabbit protein kinase Calpha (PKCalpha) gene fused to a human CD2 promoter/enhancer was introduced, and we found that immunosenescence was facilitated in these transgenic mice. In this study, we found that along with age-dependent increase in the level of protein expression of PKCalpha and its translocation to the membrane, activated T cells became less sensitive to apoptosis-inducing anti-Fas antibody. The capacity of T cells to express Fas antigen on their surfaces in response to anti-CD3 and interleukin-2 was impaired in PKCalpha-transgenic mice of relatively advanced age, although background Fas expression levels on T cells from those mice were high. We then found that out of proportion to a high level of cell surface Fas expression the density of cholera toxin B (CTx)-binding raft elements decreased in PKCalpha-transgenic mice of relatively advanced age and to a lesser extent in normal mice of advanced age. Correspondingly, the expression level of raft-associating Lck was decreased in these mice. These findings suggest for the first time that immunosenescence of T cells involves a decrease in density of cell surface CTx-binding raft elements, which might underlie a deterioration in T-cell signal pathway for either cell death or cell activation.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Cells, Cultured
- Cholera Toxin
- Disease Models, Animal
- Immune Tolerance
- Interleukin-2
- Lymphocyte Activation
- Membrane Microdomains
- Mice
- Mice, Transgenic
- Protein Kinase C
- Protein Kinase C-alpha
- Signal Transduction
- T-Lymphocytes
- fas Receptor
The intestinal lymphoid compartment of the rat is large and diverse, but the phenotype and functions of its constituent cell populations are not fully characterized. Using new methodology for the isolation and purification of rat intestinal intraepithelial lymphocytes (IELs), we previously identified a population of alphabeta- and gammadelta-TCR- NKR-P1A NK cells. These cells were almost completely restricted to the CD4-CD8- IEL population, and unlike peripheral NK cells in the rat, they were CD2-. We now report that rat intraepithelial NK (IENK) and peripheral NK cells are similar in morphology, in their ability to lyse NK-sensitive targets, and in their ability to suppress a one-way mixed lymphocyte culture. In contrast, however, intraepithelial and splenic NK cells differ markedly in two respects. First, IENK cells express high levels of ADP-ribosyltransferase 2 (a marker of regulatory T cells in the rat) and CD25, whereas peripheral NK cells do not. Second, unlike splenic NK cells, a substantial fraction of IENK cells appear to spontaneously secrete IL-4 and/or IFN-gamma. We conclude that the rat IEL compartment harbors a large population of NKR-P1A CD3- cells that function as NK cells but display an activated phenotype and unusual cytokine profile that clearly distinguish them from splenic NK cells. Their phenotypic and functional characteristics suggest that these distinctive IENK cells may participate in the regulation of mucosal immunity.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- CD3 Complex
- Cells, Cultured
- Cytotoxicity Tests, Immunologic
- Female
- Immunity, Mucosal
- Immunophenotyping
- Interferon-gamma
- Interleukin-4
- Intestinal Mucosa
- Killer Cells, Natural
- Lectins, C-Type
- Lymphocyte Culture Test, Mixed
- Male
- NK Cell Lectin-Like Receptor Subfamily B
- Rats
- Rats, Wistar
- Spleen
- Tumor Cells, Cultured
Substantial changes in both representation and function of T lymphocyte subsets have been reported with advancing age. However, till now, no systematic studies focused on age-dependent changes in the expression intensity of the major T lymphocyte surface receptors. The present study was undertaken in order to establish age-related differences in lymphocyte subpopulations by simultaneously measuring three surface antigens in young and elderly people. Peripheral blood T cell subsets from 20 healthy elderly individuals and 15 healthy young adult donors were examined by means of a quantitative three-color flow cytometry method. Activated (HLA-DR ) and memory (CD45RO ) T cells, CD3 CD7- T lymphocytes, and cells expressing natural killer (NK) markers (CD3-CD56 NK cells and CD3 CD56 T lymphocytes) were expanded, whereas T lymphocytes expressing the adhesion molecule CD62L were lower in elderly compared with young donors. In addition to alterations in the percentages of T cell subsets during senescence, several changes in the intensity expression of T cell antigens were also detected. CD3 antigen expression was downregulated on total T lymphocytes as well as on the memory T cell subset, while CD56 T cells exhibited increased CD3 levels. Moreover, CD2 expression, unchanged on NK cells, was upregulated on T lymphocytes from elderly subjects. CD3 CD7- T cells exhibited increased expression of CD8 antigen, while the intensity expression of HLA-DR on activated T cells and CD7 on both T and NK lymphocytes was decreased. T cells from elderly subjects also exhibited higher expression of CD50 and CD62L adhesion molecules as compared with young ones. These T cell antigen expression modulations during senescence, in addition to the alteration in the frequency of the various T lymphocyte subsets, could contribute to the complex remodeling of the immune function characteristic of the elderly.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Female
- Flow Cytometry
- Humans
- Immunologic Memory
- Immunophenotyping
- Killer Cells, Natural
- Lymphocyte Activation
- Male
- Middle Aged
- T-Lymphocyte Subsets
During physiological ageing changes of the immune system take place at several levels. The objective of the submitted work was to compare the ability of spontaneous restoration of selected differentiation antigens on lymphocytes in the peripheral blood stream after previous trypsin treatment in a group of healthy elderly and adult subjects. Twenty-four adults were examined (19-59 years) and 36 elderly subjects (60-90 years). Isolated lymphocytes from the peripheral blood stream were treated with trypsin and then incubated in a cultivation medium. The authors investigated the capacity of restoration of differentiation antigens CD2, CD4, CD8 and CD45RA. Antigen CD2 was not restored in any of the investigated groups to original levels. However the difference between its expression on lymphocytes before trypsin treatment and on lymphocytes after 16-hour incubation was higher in the elderly subjects 16% (p < 0.001) than in the group of adults 7% (p < 0.01). Restoration of antigen CD4 was in both investigated groups almost equal. The number of CD8 T-lymphocytes was in elderly people lower (p < 0.05), spontaneous restoration of antigen CD8 did not differ among the investigated groups and reached in both instances the baseline value. Antigen CD45RA was restored more slowly in elderly subjects, the difference between groups was at borderline of statistical significance (p < 0.0595). From the results ensues that during physiological ageing the ability of spontaneous restoration of antigens CD2 and CD45RA declines but not of antigens CD4 and CD8. So far there is no unequivocal explanation why this change occurs, it is probably conditioned by several factors. Investigation of these changes and an attempt to influence them can help to understand age-conditioned immunological dysregulation, its consequences and the possibility to influence them by treatment.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, Differentiation, T-Lymphocyte
- Humans
- In Vitro Techniques
- Middle Aged
- Trypsin
Remarkable interspecies differences in CD2 expression on B lymphocytes have been reported in mammals. Human and rat B cells lack CD2, whilst B lymphocytes in mice are CD2 . In pigs, B cells have been supposed not to express CD2. We show here, however, that CD2 is present at a low level on a prominent subset of porcine B cells. Moreover, we describe changes in the proportions of CD2 and CD2- B-cell subsets during ontogeny. Before contact with microflora, the majority of peripheral surface immunoglobulin M (sIgM ) B cells express CD2 and sIgM CD2- B cells are rare. Shortly after colonization of conventional (CV) piglets with complex intestinal microflora, numerous CD2- B cells appear in the periphery and their relative number increases with age in both CV and specific pathogen-free (SPF) pigs. However, monoassociation of germ-free (GF) piglets with a single Escherichia coli strain does not result in a significant increase of sIgM CD2- B cells in the periphery. We suggest that CD2 is down-regulated in porcine B lymphocytes upon activation with microflora in mucosa-associated lymphatic tissues. In bone marrow (BM), we identified putative porcine B-cell precursors. These cells express CD2 at low density and do not bear either the common myelomonocytic antigen or T and B-lymphocyte receptors. Similar to mouse and human pre-B cells, this lymphocyte-sized subset expresses CD25 and class II antigens. CD2 positivity of these cells indicates that CD2 is expressed earlier than sIgM during B lymphopoiesis in pigs.
MeSH Terms
- Aging
- Animals
- Antigens, Differentiation
- B-Lymphocyte Subsets
- Bone Marrow
- CD2 Antigens
- Cell Differentiation
- Escherichia coli Infections
- Female
- Flow Cytometry
- Germ-Free Life
- Immunophenotyping
- Intestines
- Leukocytes, Mononuclear
- Swine
An immunohistochemical study was performed on three groups of young cattle (21, 60 and 300 days of age). Tonsils (palatine and pharyngeal) and mucosae (nasal and oral) were removed. Eight monoclonal antibodies (specific for CD3, CD2, CD4, CD8, WC1, cell-surface IgM, cell-surface IgG and MHC class II molecules) and an avidin/biotin complex method on frozen sections were used. The immunological cytoarchitecture of bovine tonsils is similar to that of human tonsils. Nevertheless, these lymphoid tissues are not fully developed during the first weeks of life: T and B dependent areas not well-differentiated, few germinal centres, few intra-epithelial WC1 T lymphocytes. In contrast, at 2 months, tonsils possess all the elements of a mucosa-associated lymphoid tissue (MALT). Tonsillar or mucosal epithelium is infiltrated by a large number of CD8 , WC1 T lymphocytes and cells which express MHC class II molecules. Between 21 and 60 days, the number of WC1 T lymphocytes increase markedly in the tonsillar epithelium. These results accredit the hypothesis that the presence of antigens has an effect on the localization of these lymphocytes at these sites.
MeSH Terms
- Aging
- Animals
- Antigens, Differentiation
- B-Lymphocytes
- Cattle
- Histocompatibility Antigens Class II
- Humans
- Immunoglobulin G
- Immunoglobulin M
- Immunohistochemistry
- Male
- Palatine Tonsil
- T-Lymphocytes
Numerous interactions exist among the nervous, endocrine and immune systems, mediated by neurotransmitters, hormones and cytokines. The function of these systems shows patterns of circadian rhythmicity and a number of age-related changes in the 24-hour hormonal and nonhormonal rhythms have been found in older human beings. The aim of this study was to evaluate the presence of altered integration among the nervous, endocrine and immune systems in older adults. Cortisol, melatonin, thyrotropin-releasing hormone (TRH), thyroid-stimulatinghormone (TSH), free thyroxine (FT4), growth hormone (GH), insulin-like growth factor I (IGF-I) and interleukin 2 (IL-2) serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from seven healthy young subjects aged 36-58 years (mean age /- s.e. 45.28 /- 3.31) and from seven healthy old subjects aged 65-78 years (mean age /- s.e. 68.57 /- 1.91). There was a statistically significant difference between the groups in the observed values of CD20 (total B cells, higher in the young subjects, t = 2.48, P = 0.028) and CD25 (activated T cells with expression of the alpha chain of IL-2 receptor, higher in elderly subjects, t = -2.23, P = 0.045); DR T cells were also higher in elderly subjects, T=34.0, P=0.01). There was no statistically significant difference in the observed values of CD2(total T lymphocytes), CD4 (helper/inducer T cells), CD8 (suppressor/cytotoxic T cells), CD4/CD8 ratio, CD16 (natural killer cells), HLA-DR (B cells and activated T cells), TcR delta 1 (epitope of the constant domain of delta chain of T-cell receptor 1), cortisol, melatonin, TRH, TSH, FT4" GH, IGF-I, IL-2. In the group of younger subjects a clear circadian rhythm was validated for the time-qualified changes of all the factors studied, with the exception of CD16, FT4 and IL-2. In the group of elderly subjects a clear circadian rhythm was validated for the nyctohemeral changes of CD2 (with a phase delay of three hours), CD8, CD4/CD8 ratio, CD16, CD25 (in opposite phase), cortisol (with a phase delay of one hour), melatonin, TSH (with a phase delay of one hour) and GH (with a phase advance of one hour). The results of the current study show that aging is associated with enhanced responsiveness of the T cell compartment and alterations in temporal architecture of neuro-endocrine-immune system.
MeSH Terms
- Adult
- Aged
- Aging
- Circadian Rhythm
- Endocrine System
- Female
- Hormones
- Humans
- Immune System
- Lymphocyte Count
- Lymphocyte Subsets
- Male
- Middle Aged
- Nervous System Physiological Phenomena
- Neuroimmunomodulation
- Reference Values
- Secretory Rate
The aim of this study was to test the hypothesis that human thymus maintains its function as the site of early T cell development throughout life, but to a progressively diminishing extent. Mononuclear cell suspensions prepared from the samples of 39 human thymuses were analysed for the total number of cells per gram of thymus tissue, percentage of single marker-positive CD2, CD4 and CD8 cells, percentages of double-positive CD4CD8 and CD2CD8 cells, double-negative CD4CD8 cells, absolute numbers of these cells per gram of tissue, and extent of the in vitro proliferation upon stimulation with concanavalin A (Con A), phytohaemagglutinin (PHA) and pokeweed mitogen (PWM) mitogens. The main outcome measures were flow cytometric data on thymus lymphoid cell composition (according to CD classification), expressed as percentages and numbers of cells per gram of thymus tissue. The total number of mononuclear cells expressed per gram of thymus tissue exponentially decreased with age. The slope of none of the analysed cell subpopulations differed from the slope of the line constructed for age-related decline of the total number of mononuclear cells (-0.024 on a semilogarithmic scale). The thymuses of all ages contained all analysed cell subpopulations in approximately the same proportions: percentages of these cell subpopulations did not change with age, except for all CD4 (P=0.017) and double-positive CD4 CD8 (P=0.016) cells, which tended to decrease with age. The extent of proliferation of thymus cells upon stimulation with T and B cell mitogens was unrelated to age. We conclude that the thymus retains its function as the site of differentiation of T lymphocytes throughout life. With respect to the number of involved lymphoid cells, the function exponentially decreases with age.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Child
- Child, Preschool
- Female
- Humans
- Infant
- Lymphocyte Activation
- Male
- Middle Aged
- T-Lymphocytes
- Thymus Gland
Two prominent features associated with immunosenescence are thymic involution and altered T-cell phenotype and responsiveness. We have shown previously that in CD2-fas transgenic mice, in which the Fas apoptosis molecule is constituatively expressed on T cells, T-cell senescence is greatly reduced. Using a different experimental approach, the relationship between T-cell senescence and apoptosis was analyzed on human PBMCs. The results indicate that there was increased apoptosis of CD45RO- (CD45RA ) T cells upon activation. We propose that this could account for the increase in CD45RO 'memory' T cells with aging in humans. Together these results are consistent with the notion that T-cell senescence is associated with altered apoptosis and decreased T-cell responsiveness. T-cell responsiveness remained high in CD2-fas transgenic aged mice, but there was no increase in overall life span of the mice. Increased T-cell responsiveness was associated with an increased acute-phase response and amyloid A deposition in the glomerulus of these mice. These data suggest that restoration of the T-cell immune function in aged individuals must be carried out in concert with correction of other immune factors that down modulate the acute-phase response to prevent undesirable side-effects.
MeSH Terms
- Acute-Phase Reaction
- Aging
- Amyloidosis
- Animals
- Apoptosis
- Arthritis
- Autoimmunity
- CD2 Antigens
- Cellular Senescence
- Forecasting
- Humans
- Immunologic Memory
- Mice
- Mice, Transgenic
- Mycoplasma Infections
- T-Lymphocytes
- fas Receptor
A randomized double-blind trial was performed in order to assess the efficacity of differing combinations of antioxidant nutrients on biochemical parameters of vitamin and trace element status, immunological parameters and free radical metabolism in elderly long term hospitalized subjects. A total of 756 institutionalized elderly subjects were recruited in 26 nursing homes in different areas of France. Four groups were constituted, receiving daily, for 1 year, either vitamins (beta-carotene, 6 mg; vitamin C, 120 mg; and vitamin E, 15 mg), trace elements (zinc, 20 mg and selenium, 100 micrograms), trace elements associated with vitamins, or a placebo. Biochemical indicators of trace elements and vitamin status and free radical parameters were measured before and after 6 months and 1 year of supplementation. Some immunological markers were investigated initially and after 6 months of supplementation on a subsample of 134 subjects. Mean plasma levels of alpha-tocopherol, gamma-tocopherol, vitamin C, alpha-carotene, beta-carotene and copper increased significantly after 6 months of supplementation in groups receiving vitamins alone or associated with trace elements. Serum selenium concentrations were significantly increased at 6 months of supplementation, and serum zinc only after one year in the trace element groups. Serum lycopene levels were significantly decreased by trace element supplementation. A significant increase in Se-glutathione peroxidase (GPx) levels was observed in groups receiving trace elements alone or associated with vitamins. No effect was noted on superoxide dismutase (SOD) activity or TBARs production. No effect of supplementation was found for in vitro lymphocyte proliferative responses or most lymphocyte subsets, except for a significantly lower percentage of CD2 subsets observed in groups receiving mineral supplementation either alone or associated with vitamins. A significant difference in CD19 subsets was found in groups receiving trace elements. Mean IL-1 production was significantly higher after 6 months of supplementation in the vitamin groups.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Double-Blind Method
- Female
- France
- Free Radical Scavengers
- Glutathione
- Hospitalization
- Humans
- Immunity
- Male
- Nursing Homes
- Nutritional Status
- Trace Elements
- Vitamins
It is widely accepted that the haematopoietic system is a target of growth hormone action and that GH may act as a lymphokine. The expression of GH receptors (GHR) on human peripheral blood lymphocytes (PBL) has been reported previously in adult donors by dual fluorochrome flow cytometry. The aim of this study was to apply the cytofluorimetric method to the analysis of GHR expression on PBL in various human conditions characterized by different patterns of growth due to age or physiopathological conditions. PBL from 38 normal (control) subjects (7 newborns, 18 prepubertal children, 13 adults) were studied in order to provide age-related physiological data. Twenty-two short children (18 with idiopathic short stature, 4 with Ullrich-Turner syndrome) were studied to determine the expression of GHR in conditions of impaired longitudinal growth which may or may not require GH treatment. Analysis was performed using a fluorescein isothiocyanate (FITC)-conjugated antibody specific for the GHR (mAb263) and phycoerythrin (PE)-anti CD2 (T and natural killer cells) or PE-anti CD2 (B cells) in dual fluorochrome flow cytometric assays. Results were expressed as mean fluorescent intensity (MFI). Adult CD2 coils exhibited a significantly higher GHR expression (MFI 347 /- 40) than that expressed in children and newborns (MFI 285 /- 36 and 299 /- 41, respectively, P < 0.001). A significantly increased expression of GHR on CD2 cells was also found in short children (MFI 330 /- 42 vs 285 42- 36, respectively; P < 0.002), whereas Ullrich-Turner syndrome patients did not show any difference from their age and gender matched controls (254 /- 52 and 288 /- 40, respectively). A negative relationship was found between GHR expression on CD2 cells and height-SDS (r - 0.54, P < 0.0001) or BMI (r - 0.4, P < 0.015) in controls and short children, independent of their GH secretory status. Expression of GHR and CD20 cells was higher than that expressed on CD2 cells in all subjects. No appreciable differences were found in the MFI levels of GHR expression on CD20 cells either among the different age group controls or between short children or Ullrich-Turner syndrome patients. A significant downregulation of expression was shown in CD20 (P < 0.008) but not CD2 cells after 6 months of GH treatment in 6 short children who had a poor response to GH provocative tests. GH receptor expression on immune cells in non-syndromic short children appears to be inversely related to the linear growth expression and BMI of the subjects, contrary to findings with hepatic derived serum GHBP. This finding may reflect alternate exon usage in lymphoid cells, and indicates that GH has a distinctive role in the immune system.
MeSH Terms
- Adult
- Aging
- Antigens, CD20
- B-Lymphocytes
- Body Mass Index
- CD2 Antigens
- Child
- Female
- Flow Cytometry
- Growth
- Growth Disorders
- Growth Hormone
- Humans
- Infant, Newborn
- Killer Cells, Natural
- Lymphocytes
- Male
- Receptors, Somatotropin
- Reference Values
- T-Lymphocytes
We previously demonstrated that increased Fas expression in T cells of aged CD2-fas transgenic (Fas-Tg) CD-1 mice results in an increased immune response and T cell apoptosis. Surprisingly, despite prevention of T cell immune senescence, the average life span of Fas-Tg mice is comparable with that of nontransgenic (non-Tg) mice. Histopathologic evaluation of tissue sections showed that nearly 50% of the aged (>18-mo-old) Fas-Tg mice developed renal amyloid A amyloidosis, whereas no amyloid deposition was observed in aged non-Tg mice. The amyloid A deposition was observed primarily in glomeruli by using immunohistochemical stains and electron microscopy. The full-length amino acid coding sequence of serum amyloid A2 cDNA in CD-1 mice was identical to that of amyloid A amyloidosis-susceptible BALB/c mice. Although there was no significant difference in steady-state serum amyloid A level in the serum of aged non-Tg and Fas-Tg mice, challenging mice with staphylococcal enterotoxin B resulted in significantly higher serum levels of serum amyloid A on day 2 and IL-6 on days 1 and 2 and a higher magnitude of weight loss on day 7 in aged Fas-Tg mice compared with young mice. These parameters, at the indicated time points, were equivalent between young and aged non-Tg mice. Taken together, our data suggest that prevention of T cell senescence in Fas-Tg mice may be a factor in induction of an excessive acute-phase response triggered by T cell activation. The Fas-Tg mice are a novel model for understanding the immunologic mechanisms leading to secondary amyloidosis.
MeSH Terms
- Acute-Phase Reaction
- Aging
- Amino Acid Sequence
- Amyloidosis
- Animals
- Base Sequence
- CD2 Antigens
- Cellular Senescence
- Kidney Diseases
- Kidney Glomerulus
- Lymphocyte Activation
- Mice
- Mice, Inbred BALB C
- Mice, Transgenic
- Molecular Sequence Data
- Serum Amyloid A Protein
- T-Lymphocytes
- fas Receptor
Highly purified CD4 CD45RA cells from cord blood and peripheral blood from healthy adults were studied. The levels of expression of the CD2, CD3, CD4 and CD28 antigens were similar; however, CD45 and CD45RA antigen expression were slightly lower in cord cells. The reduced expression of the CD45RA antigen on cord CD4 T cells was confirmed in whole blood. Functional assessment revealed deficiencies in cord CD4 CD45RA T cells. Interleukin-2 (IL-2) production in response to specific triggering via CD2 monoclonal antibody (mAb) alone, or CD2 mAb in combination with CD28 mAb showed marked underproduction (about 10% of adult production). When CD25 expression was examined, it was observed that the proportion of activated CD4 CD45RA T cells in cord blood was lower than in adult (about 20% of adult expression). Proliferation to CD2 mAbs or CD2 28 mAbs of cord blood native cells was similarly depressed. Investigation of IL-2 mRNA expression under these stimulatory conditions paralleled the results observed for CD25 expression, IL-2 production and proliferation. When phorbol 12-myristate 13-acetate (PMA) was added to the cells triggered with CD2 28mAbs, the responses examined were enhanced in both cord and adult blood with no significant differences between the groups. These findings suggest that under identical conditions of stimulation, purified cord blood CD4 CD45RA T cells do not acquire similar activation status as their adult counterparts. These findings may help in understanding the reduced graft-versus-host disease (GVHD) observed in cord blood stem cell transplantation.
MeSH Terms
- Adult
- Aging
- CD4-Positive T-Lymphocytes
- Cell Culture Techniques
- Cell Division
- Cell Separation
- Fetal Blood
- Flow Cytometry
- Humans
- Infant, Newborn
- Interleukin-2
- Leukocyte Common Antigens
- Lymphocyte Activation
- RNA, Messenger
Involution of the thymus is a feature of age and precedes inefficient functioning of the immune system. C57BL/10 mice show an 83% reduction in number of thymocytes between 3 and 20 mo of age, with a significant decline in each of the thymic subsets defined by their expression of CD4 and CD8. The similar percentage contribution of each subset to the whole at 3, 12, and 20 mo suggests a lesion in the T cell developmental pathway within an early subset. The CD3- CD4- CD8- subset showed a significant decline in number by 20 mo of age, but despite this reduction, no significant difference was noted in the number of [[CD44]] CD25- cells, the earliest stage of this subset between 3 and 20 mo of age. A significant decline in the number of their progeny, the [[CD44]] CD25 , and the progeny of these cells, the [[CD44]]- CD25 cells, was noted by 12 mo of age. Expression of CD25 within this subset is associated with rearrangement of TCR beta-chain genes. F5 transgenic mice, carrying a complete TCR-alphabeta transgene under the control of a CD2 minigene cassette on a C57BL/10 background, showed no age-associated thymic atrophy in any of the defined thymic subsets over the same period as the normal C57BL/10 mice. Similar results were noted with mice carrying the same transgene but which in addition were also RAG-1-. The results indicate that age-associated thymic involution was associated with problems with rearrangement of the TCR beta-chain genes affecting the production of thymocytes.
MeSH Terms
- Aging
- Animals
- Atrophy
- CD3 Complex
- CD4 Antigens
- CD8 Antigens
- Cell Differentiation
- Crosses, Genetic
- Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor
- Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
- Homeodomain Proteins
- Immunophenotyping
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Proteins
- Receptors, Antigen, T-Cell
- T-Lymphocyte Subsets
- Thymus Gland
Assessment of CD2, CD4, CD8 and gamma delta cell distribution among mononuclear cells obtained from the blood and lymphoid tissues of fetal calves, 0-150-day-old calves and adult cows was the focus of this investigation. The distributions of some of the lymphocyte subsets in peripheral blood showed variation in fetal and maturing calves as well as being markedly different from those observed in adult cows. We provide evidence that as early as 1 month prepartum, fetal calves have a full complement of at least four of the major T-cell subsets found in the normal bovine. In blood, CD2( ) were significantly higher at 1, 30 and 90 days of age, CD4( ) and CD8 cells demonstrated a peak in the fetuses that dropped below adult levels from 1 to 120 days of age, and gamma delta ( ) cells were highest at birth and decreased to adult levels by 150 days of age. Except for the gamma delta ( ) cells, the subsets were significantly higher in lymphoid tissues obtained from fetal and maturing calves than in the mature animals. All four subsets were significantly higher in fetal and young calf splenic tissues. No significant differences were observed in the distribution of the four subsets in thymuses assayed in this study. An interesting pattern was seen in a longitudinal study of T-cell subsets that showed 7-8 day cyclical changes in CD2 and CD4 marked cells in adult peripheral blood.
MeSH Terms
- Aging
- Animals
- Cattle
- Cell Differentiation
- Embryonic and Fetal Development
- Female
- Flow Cytometry
- Longitudinal Studies
- Lymph Nodes
- Lymphocyte Count
- Lymphoid Tissue
- Spleen
- T-Lymphocyte Subsets
- Thymus Gland
Ageing is associated with complex remodelling in the phenotypic and functional profiles of T lymphocytes. We investigated whether expression of CD28 antigen on T cells is conserved throughout adulthood and ageing in humans. For this purpose we analysed T cells obtained from peripheral blood of 102 healthy people of ages ranging from 20 to 105 years. We found an age-related increase of CD28- T cells in percentage and absolute number, predominantly among CD8 T cells. CD28- T cells from aged donors analysed by flow cytometry appeared as resting cells (not expressing CD25, CD38, CD69, CD71, DR), bearing markers of cytotoxic activity (CD 11b and CD 57) and with a phenotype compatible with 'memory' cells (up-regulated CD2 and CD11a; CD62L absent). At the functional level, freshly isolated purified CD28- CD8 T cells showed high anti-CD3 redirected cytotoxic activity against Fc-bearing P815 cells. The same activity tested on freshly isolated bulk T lymphocytes was significantly augmented with age. We found a positive correlation between age, number of CD8 CD28- T cells and anti-CD3 redirected cytotoxicity by freshly isolated T cells. These data suggest that an activation of unknown nature within the cytotoxic arm of the immune system occurs with age. We speculate that these cytotoxic T lymphocytes (CTL) in vivo may constitute armed effector cells for immediate killing of targets bearing peptides from pathogens of intracellular origin.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD28 Antigens
- CD3 Complex
- CD8-Positive T-Lymphocytes
- Cell Separation
- Cytotoxicity, Immunologic
- Flow Cytometry
- Humans
- Lymphocyte Count
- Middle Aged
Flow cytometric analysis of lymphocyte subsets were evaluated in 391 healthy Asian subjects ranging in age from birth to 40 years. Lymphocyte subsets were analysed using specific monoclonal antibodies: CD20 (B cells), CD3 and CD2 (T cells), CD16 and CD56 (NK cells), CD4/CD3 (helper-inducer T cells), CD8/ CD3 (suppressor/cytotoxic T cells), HLA-DR expression on CD3 and CD25 (Tac) on CD3. The total white cell count, absolute lymphocyte counts, and B cell percentages peaked in infancy and declined steadily with age. Absolute counts of each subset, which were derived from absolute lymphocyte counts, also followed this trend. Increases with age were seen in the NK, T cell (CD2, CD3), and CD8 percentages. Males tended to have higher NK and CD8 percentages than females, and, conversely, females had higher CD3 and CD4 percentages than males. Comparison of our results with studies involving Caucasian subjects indicated higher NK percentages in our Asian population and lower CD4 absolute counts in the males of our population. These results indicate the presence of age, sex, and probable racial differences in lymphocyte subset expression. Our results may serve as reference standards for the Asian population.
MeSH Terms
- Adolescent
- Adult
- Aging
- Asian Continental Ancestry Group
- Child
- Child, Preschool
- China
- European Continental Ancestry Group
- Female
- Fetal Blood
- Flow Cytometry
- Humans
- Immunophenotyping
- India
- Infant
- Infant, Newborn
- Lymphocyte Count
- Lymphocytes
- Malaysia
- Male
- Sex Characteristics
It is well documented that the proliferative capacity of T cells declines with advancing age. There are, however, conflicting data as to the role of the accessory cell and whether or not this loss in responsiveness extends to all T-cell stimuli and to all T cells. We report here on the capacity of subpopulations of peripheral blood CD4 T cells from the healthy aged to proliferate in response to anti-CD2 receptor-induced activation in the complete absence of accessory cells by using various exogenous cofactors as second signals. These costimulatory factors included phorbol 12-myristate 13-acetate (PMA), interleukin (IL)-1, IL-2, IL-6 and IL-7 and the monoclonal antibodies, anti-CD28 and anti-CD44. Under these conditions, the proliferative responsiveness of CD4 CD45RO T cells from the aged was found to be comparable to young control cells for all stimuli tested, except anti-CD2 plus IL-7. This suggests that signal transduction pathways involving CD2, except IL-7-mediated events, are essentially intact in 'old' memory CD4 T cells. On the other hand, several cofactors, namely IL-2, IL-6, IL-7 and to a lesser extent IL-1 beta and PMA, failed to support adequately CD2-induced activation in 'old' CD4 CD45RA T cells suggesting severe and multiple signalling deficiencies in this subset.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- CD2 Antigens
- Cell Culture Techniques
- Cell Division
- Female
- Humans
- Interleukins
- Leukocyte Common Antigens
- Lymphocyte Activation
- Male
- T-Lymphocyte Subsets
As part of a comprehensive study of current and former US Air Force personnel, an extensive assessment of the immune system of 497 normal male subjects was conducted in 1987. Cell surface marker studies for CD2 (total T cells), CD4 (helper T cells), CD8 (suppressor T cells), CD25 (activated T cells), CD20 (total B cells), CD14 (monocytes), and HLA-DR positive cell populations were measured. The CD4/CD8 ratio was also calculated. Functional stimulation assays were also performed using phytohemagglutinin (PHA) and a culture of mixed lymphocytes. Assays of natural killer cells with and without interleukin-2 stimulation were done. In addition to the distribution and range of values for each assay, statistical analyses were performed to determine the effect of age, race, percentage body fat, tobacco use and alcohol consumption on each variable. Age and alcohol consumption had significant correlation with suppressed counts and functions on nearly all variables while tobacco use was associated with stimulation of both T-cell numbers and function. These findings highlight the importance of using age-specific ranges of normal values for these tests of immunity and the need to consider life-style factors in the interpretation of the laboratory assessment of immune status.
MeSH Terms
- Aerospace Medicine
- Aging
- Alcohol Drinking
- Cells, Cultured
- Humans
- Immune System
- Immunoglobulins
- Leukocyte Count
- Life Style
- Lymphocyte Activation
- Lymphocyte Culture Test, Mixed
- Lymphocyte Subsets
- Male
- Military Personnel
- Smoking
- T-Lymphocytes
- United States
Protein-tyrosine kinases have been implicated in signal transduction in T lymphocytes after stimulation of many cell-surface molecules, including the T-cell antigen receptor, CD4, CD8, CD2, CD5, and CD28. Yet the identities of many of these tyrosine kinases remain unknown. We have isolated a murine tyrosine kinase gene, called Tsk for T-cell-specific kinase, that appears to be exclusively expressed in T lymphocytes. The Tsk cDNA clone encodes a polypeptide of 70 kDa, which is similar in sequence to both the src and abl families of tyrosine kinases. Sequence comparisons also indicate that Tsk contains one src-homology region 2 domain and one src-homology 3 domain but lacks the negative regulatory tyrosine (src Tyr-527) common to src-family kinases. In addition, Tsk expression is developmentally regulated. Steady-state Tsk mRNA levels are 5- to 10-fold higher in thymocytes than in peripheral T cells and increase in the thymus during mouse development from neonate to adult. Furthermore, Tsk is expressed in day 14 fetal thymus, suggesting a role for Tsk in early T-lymphocyte differentiation.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Animals, Newborn
- Base Sequence
- Cell Differentiation
- Cloning, Molecular
- Gene Expression Regulation
- Genes, abl
- Genes, src
- Mice
- Molecular Sequence Data
- Molecular Weight
- Polymerase Chain Reaction
- Protein-Tyrosine Kinases
- Signal Transduction
- T-Lymphocytes
- Thymus Gland
- Tissue Distribution
Peripheral blood lymphocyte subset reference ranges were examined in a large group (N = 130) of healthy pediatric patients ranging in age from 1 month to 17 years. All samples were stained with monoclonal antibodies, processed with a whole blood lysis technique, and analyzed on a flow cytometer. Data analysis demonstrated statistically significant changes in most lymphocyte subsets at age 3 years. The relative and absolute numbers of total lymphocytes, CD2, CD4, and CD19 cells; absolute numbers of CD3 and CD8 cells; and CD4/CD8 ratios were high at birth, decreased during early childhood, and closely approximated adult reference values after age 3 years. The relative numbers of CD8 lymphocytes were low in early childhood and then rose to adult values after 3 years of age. The relative percentage of CD3 cells remained stable over all ages studied. Although "adult" lymphocyte subset reference ranges may be similar to those in children older than 3 years, age-adjusted reference ranges should be used for the early childhood period.
MeSH Terms
- Adolescent
- Aging
- Antigens, CD
- Child
- Child, Preschool
- Humans
- Infant, Newborn
- Lymphocyte Subsets
- Lymphocytes
- Reference Values
Using flow-microfluorometry analysis and cluster determinant (CD) markers, we studied how lymphocyte subpopulations in lymphoid organs of specific-pathogen-free pigs developed in pigs from birth to young adulthood. Cell suspensions of the thymus and spleen were prepared and peripheral blood cells were collected at 1, 4, 10, and 40 weeks of age. Tissue sections of the thymus and spleen were stained with monoclonal antibodies directed against CD2 and immunoglobulin to localize the CD2-Ig- lymphocyte subpopulation. In the thymus, only limited changes were observed in the lymphocyte subpopulations with time. Most thymocytes expressed CD4 or CD8 or both. Most CD2-Ig- cells or, 'null cells', (5-13%) were observed in the medulla of the thymus and probably represented a recirculating cell type. In the spleen and blood the percentage of CD2 and Ig cells increased significantly with time, the former increasing from about 30-60% owing to an increase of CD8 cells. Therefore, the selective increase of the CD8 population also caused the CD4/CD8 ratio to change. Although CD2 cells in the spleen and blood are positive for CD4 or CD8, but not for both, quantities of CD4 CD8 cells were also observed. Half of the lymphocytes in the spleen and blood were typed as null cells at 1 week of age and decreased in proportion to the increase of the CD8 and Ig cells. Nevertheless, quantities of null cells were still present in the spleen blood at 40 weeks of age. Almost all these were located in the red pulp of the spleen. This study indicates an effect of age and housing conditions on the distribution of the lymphocyte subpopulations, and especially on the CD8 subset. Quantities of CD4 CD8 cells as well as CD4-CD8- were observed in blood, but also in spleen of pigs. The function of high numbers of null cells directly after birth are discussed.
MeSH Terms
- Aging
- Animals
- Flow Cytometry
- Immunoenzyme Techniques
- Leukocyte Count
- Specific Pathogen-Free Organisms
- Spleen
- Swine
- T-Lymphocyte Subsets
- Thymus Gland
Swine possess an extraordinarily high number of T lymphocytes with the phenotype CD4-CD8- in peripheral blood as well as in lymphoid tissues. This subpopulation is subdivided into at least four subsets defined by the expression of CD2 and three biochemically distinct gamma/delta T cell receptors. The four subsets differ largely in their pattern of lymphoid homing in that CD2- subsets, historically referred to as null lymphocytes, predominate in the circulating pool, whereas CD2 subsets are enriched in lymphoid tissues. Here we document the expression of all three types of gamma/delta T cell receptors by CD4-CD8- porcine thymocytes, which provides the first evidence for a thymic origination of all subsets of porcine gamma/delta T lymphocytes. The biochemical analysis shows that three distinct gamma-chains form disulfide-bonded cell surface heterodimers with a common delta-chain and that glycosylation of all chains is already completed within the thymus. Surprisingly, CD2- subsets, which are known to be enriched among thymic emigrants and which numerically predominate in peripheral blood, are underrepresented in the thymus, suggesting a high export rate.
MeSH Terms
- Aging
- Animals
- Antigens, Differentiation, T-Lymphocyte
- Antigens, Surface
- CD2 Antigens
- CD4 Antigens
- CD8 Antigens
- Electrophoresis, Polyacrylamide Gel
- Flow Cytometry
- Phenotype
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, Immunologic
- Swine
- T-Lymphocyte Subsets
- T-Lymphocytes
- Thymus Gland
We have recently identified a dominant wave of CD4-CD8- (double-negative [DN]) thymocytes in early murine fetal development that express low affinity Fc gamma receptors (Fc gamma RII/III) and contain precursors for Ti alpha/beta lineage T cells. Here we show that Fc gamma RII/III is expressed in very immature CD4low single-positive (SP) thymocytes and that Fc gamma RII/III expression is downregulated within the DN subpopulation and before the CD3-CD8low SP stage in T cell receptor (TCR)-alpha/beta lineage-committed thymocytes. DN Fc gamma RII/III thymocytes also contain a small fraction of TCR-gamma/delta lineage cells in addition to TCR-alpha/beta progenitors. Fetal day 15.5 DN TCR-alpha/beta lineage progenitors can be subdivided into three major subpopulations as characterized by cell surface expression of Fc gamma RII/III vs. CD2 (Fc gamma RII/III CD2-, Fc gamma RII/III CD2 , Fc gamma RII/III-CD2 ). Phenotypic analysis during fetal development as well as adoptive transfer of isolated fetal thymocyte subpopulations derived from C57B1/6 (Ly5.1) mice into normal, nonirradiated Ly5.2 congenic recipient mice identifies one early differentiation sequence (Fc gamma RII/III CD2(-)-->Fc gamma RII/III CD2( )-->Fc gamma RII/III-CD2 ) that precedes the entry of DN thymocytes into the CD4 CD8 double-positive (DP) TCRlow/- stage. Unseparated day 15.5 fetal thymocytes develop into DP thymocytes within 2.5 d and remain at the DP stage for > 48 h before being selected into either CD4 or CD8 SP thymocytes. In contrast, Fc gamma RII/III CD2- DN thymocytes follow this same developmental pathway but are delayed by approximately 24 h before entering the DP compartment, while Fc gamma RII/III-CD2 display accelerated development by approximately 24 h compared with total day 15.5 thymocytes. Fc gamma RII/III-CD2 are also more developmentally advanced than Fc gamma RII/III CD2- fetal thymocytes with respect to their TCR beta chain V(D)J rearrangement. At day 15.5 in gestation, beta chain V(D)J rearrangement is mostly, if not entirely, restricted to the Fc gamma RII/III-CD2 subset of DN fetal thymocytes. Consistent with this analysis in fetal thymocytes, > 90% of adult thymocytes derived from mice carrying a disrupting mutation at the recombination-activating gene 2 locus (RAG-2-/-) on both alleles are developmentally arrested at the DN CD2- stage. In addition, there is a fivefold increase in the relative percentage of thymocytes expressing Fc gamma RII/III in TCR and immunoglobulin gene rearrangement-incompetent homozygous RAG-2-/- mice (15% Fc gamma RII/III ) versus rearrangement-competent heterozygous RAG-2 /- mice (< 3% Fc gamma RII/III ). Thus, Fc gamma RII/III expression defines an early DN stage preceding V beta(D beta)I beta rearrangement, which in turn is followed by surface expression of CD2. Loss of Fc gamma RII/III and acquisition of CD2 expression characterize a late DN stage immediately before the conversion into DP thymocytes.
MeSH Terms
- Aging
- Animals
- Antigens, Differentiation, T-Lymphocyte
- Base Sequence
- CD2 Antigens
- CD4 Antigens
- CD8 Antigens
- Cell Cycle
- Cell Separation
- DNA
- Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
- Mice
- Mice, Inbred C57BL
- Molecular Sequence Data
- Phenotype
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, IgG
- Receptors, Immunologic
- T-Lymphocyte Subsets
- Thymus Gland
The influence of ageing on phenotype and function of CD4 T cells was studied by comparing young (19-28 years of age) and aged (75-84 years of age) donors that were selected using the SENIEUR protocol to exclude underlying disease. An age-related increase was observed in the relative number of memory cells, not only on the basis of a decreased CD45RA and increased CD45RO expression, but also on the basis of a decrease in the fraction of CD27 CD4 T cells. Our observation that the absolute number of CD45RO CD4 T cells was increased, while absolute numbers of CD27-CD4 T cells remained unchanged in aged donors, indicates that the latter subset does not merely reflect the size of the CD45RO CD4 T cell pool. The increased fraction of memory cells in the aged was functionally reflected in an increased IL-4 production and T cell proliferation, when cells were activated with the combination of anti-CD2 and anti-CD28, whereas IL-2 production was comparable between both groups. No differences were observed with respect to proliferative T cell responses or IL-2 production using plate-bound anti-CD3 or phytohaemagglutinin (PHA). The observation that IL-4 production correlated with the fraction of memory cells in young donors but not in aged donors suggests different functional characteristics of this subset in aged donors.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Humans
- Immunologic Memory
- Interleukin-2
- Interleukin-4
- Leukocyte Common Antigens
- Lymphocyte Activation
- Phenotype
- T-Lymphocyte Subsets
- Tumor Necrosis Factor Receptor Superfamily, Member 7
The objective of this investigation was to determine whether an imbalance between naive- and memory-phenotype cells occurs within CD4 and/or CD8 splenic T cell subsets in models of protein-energy malnutrition (PEM) which produce wasting disease (loss of approximately 1.6% of body weight per day for 14 d) and profound depression in thymus-dependent immunity. Male and female weanling mice of disparate inbred strains, CBA/J and C57BL/6J, were allocated to the following groups: zero-time control (23 d old and 19 d old, respectively), ad libitum intake of a complete purified diet (19% crude protein, 17 kJ/g gross energy), restricted intake of the complete diet, and (C57BL/6J, only) ad libitum intake of an isocaloric low protein diet (0.6% crude protein). Surface expression of isoforms of CD45, a component of the T cell receptor complex, as well as of the accessory molecule, CD2, were assessed by flow cytometry of splenic mononuclear cell suspensions. Both major T cell subsets in the malnourished groups contained a significantly higher proportion of cells expressing the surface marker, CD45RA, than was found in the spleen cells of the control groups. CD45RA (naive-phenotype) T cells represent the extreme of quiescence and stringent activation requirements among thymic lymphocytes. The results provide the first clear evidence of a T cell subset imbalance in PEM which is consistent with depression in acquired immunity and which occurs, apart from antigenic challenge, in a site wherein immune responses take place. The T cell receptor complex may emerge as a focal point of the depressive influence of PEM on the competence of thymic lymphocytes.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- Body Weight
- CD2 Antigens
- Eating
- Female
- Flow Cytometry
- Leukocyte Common Antigens
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Phenotype
- Protein-Energy Malnutrition
- Spleen
- T-Lymphocytes
- Thymus Gland
- Weaning
T cell dysfunction and thymic involution are major immunologic abnormalities associated with aging. Fas (CD95) is a bifunctional molecule that is critical for apoptosis and stimulation during T cell development, but the role of Fas during aging has not been determined. Fas expression and function on T cells from old (22-26-mo-old) mice was compared with young (2-mo-old) mice and old CD2-fas-transgenic mice. Fas expression and ligand-induced apoptosis were decreased on T cells from old mice compared with young mice. This correlated with an age-related increase in CD44 Fas- T cells. There was a marked decrease in the proliferation of T cells from old mice after anti-CD3 stimulation compared with young mice. Anti-CD3-stimulated T cells from young mice exhibited increased production of interleukin (IL)-2 and decreased production of interferon-gamma and IL-10 compared with old mice. There was an age-related decrease in the total thymocyte count from 127 /- 10 cells in young mice compared with 26 /- 8 x 10(6) in old mice. In 26-mo-old CD2-fas-transgenic mice, Fas and CD44 expression, Fas-induced apoptosis, T cell proliferation, and cytokine production were comparable to that of the young mice. These results suggest that T cell senescence with age is associated with defective apoptosis, and that the CD2-fas transgene allows maintenance of Fas apoptosis function and T cell function in aged mice comparable to that of young mice.
MeSH Terms
- Aging
- Animals
- Antigens, Surface
- Apoptosis
- CD2 Antigens
- Carrier Proteins
- Female
- Gene Expression Regulation, Developmental
- Hyaluronan Receptors
- Immunologic Deficiency Syndromes
- Lymphocyte Count
- Male
- Mice
- Mice, Transgenic
- Receptors, Cell Surface
- Receptors, Lymphocyte Homing
- Recombinant Fusion Proteins
- Specific Pathogen-Free Organisms
- T-Lymphocyte Subsets
- Thymus Gland
- fas Receptor
Examination of the interaction between human immunodeficiency virus (HIV) regulatory gene products and the host immune system is fundamental to understanding the pathogenesis of HIV and could reveal possible targets for therapeutic intervention in the treatment of AIDS. The HIV Tat gene is a potential candidate for this type of strategy. Transgenic mice can be used to investigate the in vivo effects of Tat on the developing and dynamic immune system and on cellular gene expression. Thus, we have generated transgenic mice that harbor the HIV type 1 Tat gene under the transcriptional control of the human CD2 gene regulatory elements. This expression cassette results in high-level, tissue-specific transcription of the transgene within the T-cell compartment. In this report, we demonstrate the effects of Tat on the in vivo immune system. CD2-Tat transgenic mice show no signs of aberrant thymic development and have normal levels of T-cell subsets in the thymus and peripheral lymphoid organs. However, activated T cells from transgenic mice contain increased levels of tumor necrosis factor beta mRNA as well as biologically active tumor necrosis factor protein and express elevated levels of transforming growth factor beta and interleukin-4 receptor mRNA. These increased cytokine levels do not appear to alter mitogen- or antigen-stimulated responses or induce the formation of dermal lesions in ageing mice. Such investigations should provide insight into the combination of host immune factors mediating pathogenesis in HIV infection.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Cytokines
- Exons
- Flow Cytometry
- Gene Expression
- Gene Products, tat
- Genes, tat
- HIV-1
- Humans
- Lymph Nodes
- Lymphotoxin-alpha
- Mice
- Mice, Transgenic
- RNA, Messenger
- Receptors, Interleukin
- Receptors, Interleukin-4
- Restriction Mapping
- Spleen
- T-Lymphocytes
- Thymus Gland
- Transcription, Genetic
- Transforming Growth Factor beta
- Tumor Necrosis Factor-alpha
- tat Gene Products, Human Immunodeficiency Virus
While there is accumulating evidence to indicate the presence of functional abnormalities in T cells from aged healthy humans, their cellular basis remains unclear. By using two-color immunofluorescence and multiparameter flow cytometry we show that (a) the number of peripheral blood antigen receptor-positive (TcR-CD3 ) T cells is significantly lower in aged than in young adults; (b) the numbers of E-rosette-forming (CD2 ) cells are maintained in the elderly due to a reciprocal increase in the frequency of TcR-CD3- cells, which constitute only a minor lymphocyte subpopulation in young adults, and (c) TcR-CD3-CD2 5- lymphocytes exhibit the phenotypic features of natural killer (NK) cells. By using functional assays we show the TcR-CD3-CD2 16 lymphocytes are indeed NK cells because they are activated by and lyse NK targets. In contrast, they are unresponsive to either phytohemagglutinin or mitogenic CD2 monoclonal antibody stimulation, which in turn activates TcR-CD3 CD2 16- T cells. We conclude that the increase in TcR-CD3-CD2 NK cells masks the T cell reduction in aged humans by normalizing CD2 cell frequencies. However, NK cells cannot functionally substitute the thymus-derived lymphocytes they replace.
MeSH Terms
- Aged
- Aging
- Antigens, Differentiation
- Antigens, Differentiation, T-Lymphocyte
- CD2 Antigens
- CD3 Complex
- CD5 Antigens
- Cytotoxicity, Immunologic
- Humans
- Immunity, Cellular
- Killer Cells, Natural
- Lymphocyte Activation
- Receptors, Antigen, T-Cell
- Receptors, Immunologic
- T-Lymphocytes
Recent studies have focused on the potential role of accessory molecules such as CD2, CD28, Thy-1, or TAP in the delivery of activating signals to thymocytes through antigen-independent pathways. To better understand the molecular interactions involved in the expansion of early thymic immigrants, rat mAb were raised against murine thymocyte-surface molecules and screened for their capacity to trigger thymocyte proliferation. One of these mAb (H194-112, IgG2a) was found to recognize a novel heterodimeric thymocyte-activating molecule (THAM) of Mr = 110,000 to 128,000. Flow cytometric analyses and staining patterns on frozen thymus sections subdivided adult thymocytes in three subsets expressing THAM at either low (10%), moderate (80%), or high (5 to 8%) cell-surface density; these cell groups were found to correspond, respectively, to the medullary, the cortical, and the immature CD4-CD8-, J11d thymocytes, in which the T cell precursor pool is included. Moreover, most (90%) day 16 fetal thymocytes were also found to upregulate THAM cell-surface expression. The THAMhigh cells were localized in the subcapsular area of the neonatal thymus and scattered throughout the adult organ. Cross-linked mAb H194-112 induced the proliferation of both immature and mature thymocytes in the presence of either PMA or IL-1 and IL-2. The observation that early thymocytes up-regulate THAM along with the IL-2R suggests that this molecule might be involved in an important activation pathway during thymocyte differentiation.
MeSH Terms
- Aging
- Animals
- Antibodies, Monoclonal
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- Epitopes
- Interleukin-2
- Lectins, C-Type
- Lymphocyte Activation
- Mice
- Mice, Inbred BALB C
- Phenotype
- Rats
- T-Lymphocytes
- Thymoma
- Thymus Gland
The expression of c-fos, c-jun and jun B proto-oncogenes was studied in phytohemagglutinin (PHA) activated peripheral blood lymphocytes (PBL) from young and aged humans. Specific mRNAs for c-fos and c-jun were detectable within 30 min after cell activation and reached maximal levels within 2 h. Both c-fos and jun B mRNAs decreased to pre-activation levels within 6 h, while c-jun mRNA remained elevated. In PHA-activated PBL, no age-related differences were observed in c-fos or jun B mRNA expression. However, c-jun mRNA levels decreased significantly (1.73 /- 0.08 vs. 1.16 /- 0.09 arbitrary units, P < 0.01, young vs. old) in PBL from elderly individuals activated with PHA. Because previous work has demonstrated that T cells from elderly individuals may display normal proliferative responses when activated via the anti-CD2 pathway, c-jun and jun B mRNA expression was also studied in anti-CD2-activated purified T cells. No age-related differences were found in the expression of either of these two proto-oncogenes by anti-CD2 activated T cells. These results suggest that the decreased IL-2 production and proliferative response displayed by PHA-activated PBL from elderly adults may be related to age-related changes in c-jun mRNA expression and in the ratio of c-fos to c-jun mRNA.
MeSH Terms
- Adult
- Aged
- Aging
- Female
- Humans
- Lymphocytes
- Male
- Middle Aged
- Phytohemagglutinins
- Proto-Oncogene Proteins c-fos
- Proto-Oncogene Proteins c-jun
- RNA, Messenger
- T-Lymphocytes
The ontogeny of the peripheral blood mononuclear cells' responsiveness to various activators during childhood was studied and compared to the expression of CDw29 and CD45RA molecules at the surface of CD4 T cells. The results show that newborn peripheral blood mononuclear cells are characterized by a responsiveness to mitogens that is higher than that observed in adults, at least shortly after stimulation. This contrasts with a clear decreased response to CD2 and CD3 MAb at any time after stimulation. These functional characteristics correlate with a low density of CDw29 antigen on virtually all CD4 T cells and a high density of CD45RA antigen on most CD4 T cells at birth. These patterns of reactivity and phenotype are similar to those found among naive adult T cells. When ageing, the response to mitogens becomes rapidly similar to the adult's values, whereas the responses to CD2 or CD3 MAb are more gradually acquired. This slow rate of functional changes grossly parallels the increase of CDw29 CD4 and the decrease of CD45RA CD4 T cell subsets. These changes finally lead to the immunophenotypic and functional characteristics that are typical of adult memory T cells. These results suggest that iterative antigenic stimulations both induce memory T cells and create the conditions to improve the overall immune competence.
MeSH Terms
- Adolescent
- Adult
- Aging
- Antibodies, Monoclonal
- Antigens, CD
- CD4 Antigens
- Cell Differentiation
- Child
- Child, Preschool
- Histocompatibility Antigens
- Humans
- Immune System
- Infant
- Infant, Newborn
- Integrin beta1
- Leukocyte Common Antigens
- Lymphocyte Activation
- T-Lymphocytes
Using immunohistological techniques, we studied the development over time of B- and T-cell compartments in the lymphoid organs of specific-pathogen-free pigs. Tissue samples were collected at various time-points, starting 2 days before the pigs were born until the pigs were 10 months old. The samples were collected from the spleen, thymus, peripheral lymph node, mesenteric lymph node, duodenum, jejunum, ileum, jejunal Peyer's patch and ileal Peyer's patch. Monoclonal antibodies specific to B- and T-cells were used to identify where the following cells were localized: IgM-B cells (cells positive to surface immunoglobulin), IgM-, IgG- and IgA-containing cells (cells positive to cytoplasmic immunoglobulin), and CD2-, CD4- and CD8-positive cells. The development of the B- and T-cell subpopulations in each organ was analysed. Two days before birth, most organs contained quantities of IgM-B cells. The spleen, lymph nodes, Peyer's patches and, notably, the thymus, contained some immunoglobulin-containing cells (Ig-CC); this finding indicates that pigs have cells that secrete immunoglobulins before birth. Just after birth, the incidence of Ig-CC increased in most organs; first IgM-CC increased, then either IgG- or IgA-CC increased, depending on the organ. T-cell development was observed clearly in spleen and in the lamina propria of the small intestine, in contrast to other organs, in which the T-cell compartments containing various T-cell subpopulations were well developed before birth. Comparison of the incidence of CD4 and CD8 cells showed that the CD4:CD8 ratio of these cells in the spleen, lymph nodes, Peyer's patches and small intestine is low, especially in adult pigs, compared with the CD4:CD8 ratio in other species. Weaning had little influence on the incidence of B- and T-cells in lymphoid organs. This study is the first immunohistological survey to describe the development of the major B- and T-cell subpopulations in various lymphoid organs of pigs, and it should be useful for future immunopathological and comparative immunological studies in pigs.
MeSH Terms
- Aging
- Animals
- Antigens, Differentiation, T-Lymphocyte
- Antigens, Surface
- B-Lymphocytes
- CD2 Antigens
- CD4-CD8 Ratio
- CD4-Positive T-Lymphocytes
- Immunoenzyme Techniques
- Immunoglobulins
- Leukocyte Count
- Lymphoid Tissue
- Membrane Glycoproteins
- Receptors, Immunologic
- Specific Pathogen-Free Organisms
- Swine
- T-Lymphocytes
- T-Lymphocytes, Regulatory
The ability of purified T cells to be activated by immobilized anti-CD3 and soluble anti-CD2 monoclonal antibodies (mAbs) was compared using cells from young and old donors. Purified T cells from elderly humans activated with immobilized anti-CD3 mAb incorporated less [3H]thymidine (58,780 vs 92,258 cpm; p < 0.02) into cellular DNA, and secreted less IL-2 into the culture supernatants than did T cells from young donors. In contrast, T cells activated with anti-CD2 mAbs displayed no age-related differences in proliferation or IL-2 production. Anti-CD2 stimulation resulted in equal IL-2 synthesis by cells from young and old donors that was comparable to the amount produced by cells from elderly donors stimulated with immobilized anti-CD3. Northern blot analysis of early cell cycle gene expression by anti-CD2 activated T cells demonstrated no age differences in the expression of p55 IL-2R or c-myc specific mRNA, although T cells from elderly individuals activated with immobilized anti-CD3 showed statistically significant decreases in both mRNAs. T cell receptor beta chain mRNA levels did not differ between cells from young or old donors after activation by either anti-CD3 or anti-CD2. The discordance in proliferative ability, IL-2 secretion, and specific mRNA expression between T cells from elderly donors activated through the CD3-TCR complex or by soluble anti-CD2 mAbs provides additional evidence for a multifactorial causation of age-related T cell proliferative defects, and may indicate that the difference in proliferative ability is, in part, attributable to responsiveness to secreted IL-2.
MeSH Terms
- Adult
- Aged
- Aging
- Antibodies, Monoclonal
- Antigens, Differentiation, T-Lymphocyte
- CD2 Antigens
- CD3 Complex
- Female
- Gene Expression
- Genes, myc
- Humans
- In Vitro Techniques
- Interleukin-2
- Lymphocyte Activation
- Male
- Middle Aged
- RNA, Messenger
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, Immunologic
- Receptors, Interleukin-2
- T-Lymphocytes