CD86
T-lymphocyte activation antigen CD86 precursor (Activation B7-2 antigen) (B70) (BU63) (CTLA-4 counter-receptor B7.2) (FUN-1) (CD86 antigen) [CD28LG2]
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With the aging population rapidly increasing worldwide, preventive measures and treatments for age-related cognitive decline and dementia are of utmost importance. We have previously demonstrated that the consumption of iso-α-acids (IAA), which are hop-derived bitter compounds in beer, prevents the formation of disease pathology in a transgenic mouse model of Alzheimer's disease (AD). However, the effect of IAA consumption on age-related cognitive decline is unknown. In the present study, we examined the effect of long-term and short-term dietary consumption of IAA, on age-related memory impairments and inflammation in the hippocampus of aged mice. When compared with young mice, aged mice showed impairment in spatial working memory during the Y-maze spontaneous alternation test, impairment in object recognition memory during the novel object recognition test (NORT), a pro-inflammatory hippocampal microglial phenotype with increased CD86 expression and inflammatory cytokine production, increased levels of glutamate and amyloid β , and decreased levels of dopamine (DA). In aged mice fed IAA for 3 months, the age-related alterations in memory, microglial inflammation, and glutamate, amyloid β , and DA levels were all significantly attenuated. Additionally, the oral administration of IAA for 7 days in aged mice with memory impairment, also improved spatial and object recognition memory. These results suggest that IAA consumption prevents inflammation in the hippocampus and ameliorates age-related cognitive decline.
Keywords
- aging
- cognitive decline
- hippocampus
- inflammation
- iso-α-acids
- memory
Aging is a significant risk factor for dry eye. Here we used a murine aging model to investigate the effects of aging on antigen presenting cells (APCs) and generation of pathogenic T helper (Th)-1 cells. Our results showed that APCs from aged mice accumulate at the conjunctiva, have higher levels of co-activation marker CD86 and lower aldehyde dehydrogenase activity. Using topical ovalbumin peptide as a surrogate antigen, we observed an increased number of antigen-loaded APCs in the draining cervical lymph nodes in the aged group and loss of tight junction protein occludin in the conjunctiva. Aged cervical lymph nodes APCs showed a greater generation of Th1 cells than young APCs in antigen-presentation assays in vitro. Aged lacrimal glands, and draining nodes showed an accumulation of IFN-γ producing CD4 T cells, while Th-17 cells were present only in aged draining nodes. There was also an age-related increase in CD4 CXCR3 IFN-γ cells in the conjunctiva, nodes, and lacrimal glands while CD4 CCR6 IL-17A cells increased in the draining nodes of aged mice. Adoptive transfer of aged CD4 CXCR3 cells into young, naive immunodeficient recipients caused greater goblet cell loss than young CD4 CXCR3 donor cells. Our results demonstrate that age-associated changes in APCs are critical for the pathogenesis of age-related dry eye.
MeSH Terms
- Adoptive Transfer
- Aging
- Animals
- Antigen-Presenting Cells
- Biomarkers
- Cellular Senescence
- Cytokines
- Disease Models, Animal
- Dry Eye Syndromes
- Female
- Lymphocyte Activation
- Mice
- Mice, Knockout
- Th1 Cells
Amongst the major features of aging are chronic low grade inflammation and a decline in immune function. The Mediterranean diet (MedDiet) is considered to be a valuable tool to improve health status, and although beneficial effects have been reported, to date, immunological outcomes have not been extensively studied. We aimed to test the hypothesis that 1 year of a tailored intervention based on the MedDiet with vitamin D (10 μg/day) would improve innate immune responses in healthy elderly subjects (65-79 years) from the English cohort (272 subjects recruited) of the NU-AGE randomized, controlled study (clinicaltrials.gov, NCT01754012). Of the 272 subjects forming the United Kingdom cohort a subgroup of 122 subjects (61 in the intervention group and 61 in the control group) was used to evaluate [i]ex vivo[/i] innate immune response, phenotype of circulating immune cells, and levels of pro- and anti-inflammatory markers. Odds Ratio (OR) was calculated for all the parameters analyzed. After adjustment by gender, MedDiet-females with a BMI < 31 kg/m had a significant upregulation of circulating CD40 CD86 cells (OR 3.44, 95% CI 1.01-11.75, [i]P[/i] = 0.0437). Furthermore, in all MedDiet subjects, regardless of gender, we observed a MedDiet-dependent changes, although not statistically significant of immune-critical parameters including T cell degranulation, cytokine production and co-receptor expression. Overall, our study showed that adherence to an individually tailored Mediterranean-like dietary pattern with a daily low dose of vitamin D3 supplements for 1 year modified a large variety of parameters of immune function in healthy, elderly subjects. We interpreted these data as showing that the MedDiet in later life could improve aspects of innate immunity and thus it could aid the design of strategies to counteract age-associated disturbances. clinicaltrials.gov, NCT01754012.
Keywords
- NU-AGE
- aging
- dietary intervention
- elderly
- inflammation
- nutrition
C-reactive protein (CRP) is the prototypical acute phase reactant, increasing in blood concentration rapidly and several-fold in response to inflammation. Recent evidence indicates that CRP has an important physiological role even at low, baseline levels, or in the absence of overt inflammation. For example, we have shown that human CRP inhibits the progression of experimental autoimmune encephalomyelitis (EAE) in CRP transgenic mice by shifting CD4 T cells away from the T 1 and toward the T 2 subset. Notably, this action required the inhibitory Fcγ receptor IIB (FcγRIIB), but did not require high levels of human CRP. Herein, we sought to determine if CRP's influence in EAE might be explained by CRP acting on dendritic cells (DC; antigen presenting cells known to express FcγRIIB). We found that CRP (50 µg/ml) reduced the yield of CD11c bone marrow-derived DCs (BMDCs) and CRP (≥5 μg/ml) prevented their full expression of major histocompatibility complex class II and the co-stimulatory molecules CD86 and CD40. CRP also decreased the ability of BMDCs to stimulate antigen-driven proliferation of T cells [i]in vitro[/i]. Importantly, if the BMDCs were genetically deficient in mouse FcγRIIB then (i) the ability of CRP to alter BMDC surface phenotype and impair T cell proliferation was ablated and (ii) CD11c-driven expression of a human [i]FCGR2B[/i] transgene rescued the CRP effect. Lastly, the protective influence of CRP in EAE was fully restored in mice with CD11c-driven human FcγRIIB expression. These findings add to the growing evidence that CRP has important biological effects even in the absence of an acute phase response, i.e., CRP acts as a tonic suppressor of the adaptive immune system. The ability of CRP to suppress development, maturation, and function of DCs implicates CRP in the maintenance of peripheral T cell tolerance.
MeSH Terms
- Animals
- C-Reactive Protein
- CD11c Antigen
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Dendritic Cells
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental
- Humans
- Lymphocyte Activation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Multiple Sclerosis
- Peripheral Tolerance
- Receptors, IgG
Keywords
- acute phase response
- aging
- autoimmunity
- inflammaging
- inflammation
- transgenic
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutations in the dystrophin gene, affecting 1:3500-5000 boys worldwide. The lack of dystrophin induces degeneration of muscle cells and elicits an immune response characterized by an intensive secretion of pro-inflammatory cytokines. Immunoglobulins modulate the inflammatory response through several mechanisms and have been widely used as an adjuvant therapy for autoimmune diseases. Here we evaluated the effect of immunoglobulin G (IG) injected intraperitoneally in a severely affected double knockout (dko) mouse model for Duchenne muscular dystrophy. The IG dko treated mice were compared regarding activity rates, survival and histopathology with a control untreated group. Additionally, dendritic cells and naïve lymphocytes from these two groups and WT mice were obtained to study in vitro the role of the immune system associated to DMD pathophysiology. We show that IG therapy significantly enhances activity rate and lifespan of dko mice. It diminishes muscle tissue inflammation by decreasing the expression of costimulatory molecules MHC, CD86 and CD40 and reducing Th1-related cytokines IFN-γ, IL-1β and TNF-α release. IG therapy dampens the effector immune responses supporting the hypothesis according to which the immune response accelerates DMD progression. As IG therapy is already approved by FDA for treating autoimmune disorders, with less side-effects than currently used glucocorticoids, our results may open a new therapeutic option aiming to improve life quality and lifespan of DMD patients.
MeSH Terms
- Animals
- Cells, Cultured
- Cytokines
- Dendritic Cells
- Dystrophin
- Humans
- Immunoglobulin G
- Immunotherapy
- Injections, Intraperitoneal
- Longevity
- Lymphocytes
- Mice
- Mice, Inbred mdx
- Muscular Dystrophy, Duchenne
- Phenotype
- Utrophin
The purpose of this study was to investigate the effects of melatonin on selected biomarkers of innate and humoral immune response as well as the antioxidant/oxidant status (superoxide dismutase-SOD and reduced glutathione levels (GSH) to understand whether age-related changes would influence the development of acute Trypanosoma cruzi (T. cruzi) infection. Young- (5 weeks) and middle-aged (18 months) Wistar rats were orally treated with melatonin (gavage) (05 mg/kg/day), 9 days after infection. A significant increase in both SOD activity and GSH levels was found in plasma from all middle-aged melatonin-treated animals. Melatonin triggered enhanced expression of major histocompatibility class II (MHC-II) antigens on antigen-presenting cell (APC) and peritoneal macrophages in all treated animals. High levels of CD4 CD28-negative T cells (*P<.05) were detected in middle-aged control animals. Melatonin induced a significant reduction (***P<.001) in CD28-negative in CD4 and CD8 T cells in middle-aged control animals. Contrarily, the same group displayed upregulated CD4 CD28 T and CD8 CD28 T cells. Melatonin also triggered an upregulation of CD80 and CD86 expression in all young-treated groups. Significant percentages of B and spleen dendritic cells in middle-aged infected and treated animals were observed. Our data reveal new features of melatonin action in inhibiting membrane lipid peroxidation, through the reduction in 8-isoprostane, upregulating the antioxidant defenses and triggering an effective balance in the antioxidant/oxidant status during acute infection. The ability of melatonin to counteract the immune alterations induced by aging added further support to its use as a potential therapeutic target not only for T. cruzi infection but also for other immunocompromised states.
MeSH Terms
- Aging
- Animals
- Antioxidants
- CD28 Antigens
- Chagas Disease
- Macrophages, Peritoneal
- Male
- Melatonin
- Oxidative Stress
- Oxidoreductases
- Rats
- Rats, Wistar
Keywords
Trypanosoma cruzi
- antioxidant protection
- immune response
- melatonin
Rats of Albino Oxford (AO) strain in our animal facility exhibit a longer average healthy life span than rats of Dark Agouit (DA) strain. Since chronic activation of macrophages contributes to chronic low level inflammation common in older age, elucidation of the changes in middle-aged rats could be useful in prevention of unbalanced inflammatory response in advanced age. We have analysed the phenotype of unelicited and thioglycollate-elicited peritoneal macrophages from young and middle-aged DA and AO rats and tested functions of these cells following stimulation with lipopolysaccharide (LPS) in vitro. Unelicited cells from middle-aged DA rats produced higher amounts of proinflammatory mediators interleukin-6 (IL-6) and nitric oxide (NO), but have a diminished response to LPS stimulation then cells from young rats, in spite of increased frequency of TLR4- and CD14-expressing mature macrophages. Injection of thioglycollate robustly increased overall cytokine production in young rats' macrophages, while diminishing their response to LPS stimulation. In middle-aged DA rats injection of thioglycollate diminished IL-6 production, but increased it in response to LPS stimulation. Quite the contrary to DA rats, the macrophages from middle-aged AO rats have released diminished levels of TNF-α and NO, whereas urea production was strongly increased, when compared to the macrophages from young rats. Although the thioglycollate injection has increased the proportion of CD86 MHCII mature macrophages in young rats, and percentages of activated TLR4 macrophages in both age groups of AO rats, it has not affected the cytokine production in young rats' macrophages, and the TNF-α production in middle-aged rats' macrophages. Moreover, the injection of thioglycollate has robustly increased the production of urea in macrophages derived from both age groups of AO rats. Although middle-aged rats of both strains were healthy during experiment, differences between the inflammatory responses of peritoneal macrophages of middle-aged rats of these strains might be one of the contributing factors defining their health in their advanced age. Development of strategies for the prevention of undesirable inflammatory changes in the elderly would benefit from the prospective study of the middle-aged.
MeSH Terms
- Aging
- Animals
- Interleukin-6
- Lipopolysaccharides
- Macrophages, Peritoneal
- Male
- Nitric Oxide
- Peritonitis
- Rats
- Rats, Inbred Strains
- Thioglycolates
- Tumor Necrosis Factor-alpha
Keywords
- Macrophages
- Rat strains
- Thioglycollate-induced peritonitis
- Young and middle-aged rats
To cope with immune responses, tumour cells implement elaborate strategies such as adaptive resistance and induction of T-cell exhaustion. T-cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of co-stimulatory molecules to T-cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukaemia-derived co-stimulatory signals on CD4 T helper (Th) cell exhaustion, which may limit anti-tumour immunity. Here, CD86 and inducible T-cell co-stimulator ligand (ICOS-LG) co-stimulatory molecules that are found on myeloid leukaemia cells supported Th cell activation and proliferation. However, under continuous stimulation, T cells co-cultured with leukaemia cells, but not with peripheral blood monocytes, became functionally exhausted. These in vitro-generated exhausted Th cells were defined by up-regulation of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitory receptors. They were reluctant to proliferate upon re-stimulation and produced reduced amounts of interleukin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Nonetheless, IL-2 supplementation restored the proliferation capacity of the exhausted Th cells. When the co-stimulation supplied by the myeloid leukaemia cells were blocked, the amount of exhausted Th cells was significantly decreased. Moreover, in the bone marrow aspirates from patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), a subpopulation of Th cells expressing PD-1, TIM-3 and/or LAG3 was identified together with CD86 and/or ICOS-LG myeloid blasts. Collectively, co-stimulatory signals derived from myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in Th cells.
MeSH Terms
- Adult
- Aged
- Antigens, CD
- CD4-Positive T-Lymphocytes
- Cell Line, Tumor
- Coculture Techniques
- Cytokines
- Female
- Hepatitis A Virus Cellular Receptor 2
- Humans
- Immunosenescence
- Leukemia, Myeloid
- Male
- Middle Aged
- Programmed Cell Death 1 Receptor
- Tumor Escape
- Up-Regulation
- Young Adult
Keywords
- T-cell immunoglobulin and mucin domain-containing protein-3
- cancer
- helper T cell
- immune escape
- interleukin-2
- lymphocyte activation gene 3
- programmed cell death 1
Mesothelioma is an almost invariably fatal tumor with chemotherapy extending survival by a few months. One immunotherapeutic strategy is to target dendritic cells (DCs), key antigen-presenting cells involved in antigen presentation, to induce antigen-specific T cell responses. However, DC-targeting will only be effective if DCs are fit-for-purpose, and the functional status of DCs in mesothelioma patients was not clear. We found that mesothelioma patients have significantly decreased numbers of circulating myeloid (m)DC1 cells, mDC2 cells and plasmacytoid (p)DCs relative to healthy age and gender-matched controls. Blood monocytes from patients could not differentiate into immature monocyte-derived DCs (MoDCs), indicated by a significantly reduced ability to process antigen and reduced expression of costimulatory (CD40, CD80 and CD86) and MHC (HLA-DR) molecules, relative to controls. Activation of mesothelioma-derived MoDCs with LPS /-IFNγ generated partially mature MoDCs, evident by limited upregulation of the maturation marker, CD83, and the costimulatory markers. Attempts to rescue mesothelioma-derived DC function using CD40Ligand(L) also failed, indicated by maintenance of antigen-processing capacity and limited upregulation of CD40, CD83, CD86 and HLA-DR. These data suggest that mesothelioma patients have significant numerical and functional DC defects and that their reduced capacity to process antigen and reduced expression of costimulatory molecules could induce anergized/tolerized T cells. Nonetheless, survival analyses revealed that individuals with mesothelioma and higher than median levels of mDC1s and/or whose MoDCs matured in response to LPS, IFNγ or CD40L lived longer, implying their selection for DC-targeting therapy could be promising especially if combined with another treatment modality.
Keywords
- Aging
- CD40Ligand
- Mesothelioma
- immunotherapy
- myeloid dendritic cells
- plasmacytoid dendritic cells
- survival outcomes
B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL( )MHC class-I(Hi)CD86(Hi)B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-γR1 on B1a cells to subsequently upregulate membrane TNF-α and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8( )T cells by targeting TNFR2 via membrane TNF-α and providing costimulation with CD86. Thus, for the first time, to our knowledge, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor-supporting activity and become inducers of potentially antitumor and autoimmune CD8( )T cells.
MeSH Terms
- 4-1BB Ligand
- Adult
- Aged
- Aging
- Animals
- Autoimmunity
- B-Lymphocyte Subsets
- B7-2 Antigen
- CD8-Positive T-Lymphocytes
- Cells, Cultured
- Cellular Senescence
- Enzyme Activation
- Female
- Granzymes
- Histocompatibility Antigens Class I
- Humans
- Lymphocyte Activation
- Macrophages, Peritoneal
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Monocytes
- Neoplasms
- Receptors, Interferon
- Receptors, Tumor Necrosis Factor, Type II
- Tumor Necrosis Factor-alpha
Although monocytes and macrophages could serve as new therapeutic targets for treatment of Alzheimer's disease (AD) and aging of the human innate immune system, its role in the pathogenesis of neurodegenerative disorders such as AD are only poorly understood. We have addressed this here by determining the number of CD14 monocytes and the frequency of HLA-DR-, CD80-, and CD86-expression in peripheral blood from healthy volunteers aged 20-79 years, and in AD patients at diagnosis and after 12, 30, and 52 weeks of rivastigmine treatment. While the number of CD14 monocytes remained constant, the expression of HLA-DR, CD80, and CD86 by monocytes increased with age. However, no differences were identified by comparing AD patients with age-matched healthy controls or following treatment of AD patients with rivastigmine. These results indicate that changes in the expression of HLA-DR, CD80, and CD86 are caused by immunosenescence rather than by AD pathology or treatment of AD patients with rivastigmine.
MeSH Terms
- Adult
- Aged
- Aging
- Alzheimer Disease
- Analysis of Variance
- Antigens, CD
- B7-1 Antigen
- B7-2 Antigen
- Cholinesterase Inhibitors
- Female
- HLA-DR Antigens
- Humans
- Lipopolysaccharide Receptors
- Male
- Middle Aged
- Monocytes
- Rivastigmine
- Young Adult
Keywords
- Alzheimer’s disease
- CD80
- CD86
- HLA-DR
- monocytes
Aims of this study were to investigate the ability of RACK1 pseudosubstrate alone or in combination with classical immune stimuli to activate human leukocytes, and to restore age-associated immune defects.A total of 25 donors (17 old donors, 77-79 yrs; 8 young donors, 25-34 yrs) were enrolled. To evaluate the effect of RACK1 pseudosubstrate on cytokine production and CD86 expression the whole blood assay was used. Cultures were treated with RACK1 pseudosubstrate in the presence or absence of lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) and incubated for 24 h or 48 h for LPS-induced CD86 expression, TNF-α, IL-6, IL-8, IL-10 production, and PHA-induced IL-4, IL-10, IFN-γ, respectively. RACK1 pseudosubstrate alone induced IL-6, IL-8, and CD86 expression in both young and old donors, and IFN-γ in old donors. In combination with LPS an increase in IL-8, IL-10 and TNF-α was observed, also resulting in restoration of age-associated defective production, while no changes in the other parameters investigated were found.Even if based on a small sample size, these results suggest the possibility to by-pass some of age-associated immune alterations, which may be beneficial in situations were natural immune stimulation is required, and highlight a different role of PKCβ in immune cells activation.
MeSH Terms
- Adjuvants, Immunologic
- Adult
- Age Factors
- Aged
- Aging
- B7-2 Antigen
- Cell Line
- Cytokines
- Endotoxins
- Enzyme Activation
- Female
- GTP-Binding Proteins
- Humans
- Leukocytes
- Male
- Neoplasm Proteins
- Peptide Fragments
- Phytohemagglutinins
- Protein Kinase C beta
- Protein Structure, Tertiary
- Receptors for Activated C Kinase
- Receptors, Cell Surface
- Substrate Specificity
- Time Factors
Keywords
- PKC
- cytokines
- immunosenescence
- signal transduction
- whole blood assay
Zinc deficiency results in immune dysfunction and promotes systemic inflammation. The objective of this study was to examine the effects of zinc deficiency on cellular immune activation and epigenetic mechanisms that promote inflammation. This work is potentially relevant to the aging population given that age-related immune defects, including chronic inflammation, coincide with declining zinc status. An in vitro cell culture system and the aged mouse model were used to characterize immune activation and DNA methylation profiles that may contribute to the enhanced proinflammatory response mediated by zinc deficiency. Zinc deficiency upregulated cell activation markers ICAM1, MHC class II, and CD86 in THP1 cells, which coincided with increased IL1β and IL6 responses following LPS stimulation. A decreased zinc status in aged mice was similarly associated with increased ICAM1 and IL6 gene expression. Reduced IL6 promoter methylation was observed in zinc-deficient THP1 cells, as well as in aged mice and human lymphoblastoid cell lines derived from aged individuals. Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Our results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation.
MeSH Terms
- Aging
- Animals
- Cells, Cultured
- DNA Methylation
- Female
- Humans
- Inflammation
- Intercellular Adhesion Molecule-1
- Interleukin-6
- Macrophage Activation
- Macrophages
- Mice
- Mice, Inbred C57BL
- Promoter Regions, Genetic
- Zinc
Keywords
- Aging
- DNA methylation
- Epigenetics
- Inflammation
- Zinc
Regulatory T-cell (Treg, CD4( ) CD25( )) dysfunction is suspected to play a key role in immune senescence and contributes to increased susceptibility to diseases with age by suppressing T-cell responses. FoxP3 is a master regulator of Treg function, and its expression is under control of several epigenetically labile promoters and enhancers. Demethylation of CpG sites within these regions is associated with increased FoxP3 expression and development of a suppressive phenotype. We examined differences in FoxP3 expression between young (3-4 months) and aged (18-20 months) C57BL/6 mice. DNA from CD4( ) T cells is hypomethylated in aged mice, which also exhibit increased Treg numbers and FoxP3 expression. Additionally, Treg from aged mice also have greater ability to suppress effector T-cell (Teff) proliferation in vitro than Tregs from young mice. Tregs from aged mice exhibit greater redox remodeling-mediated suppression of Teff proliferation during coculture with DCs by decreasing extracellular cysteine availability to a greater extent than Tregs from young mice, creating an adverse environment for Teff proliferation. Tregs from aged mice produce higher IL-10 levels and suppress CD86 expression on DCs more strongly than Tregs from young mice, suggesting decreased T-cell activity. Taken together, these results reveal a potential mechanism of higher Treg-mediated activity that may contribute to increased immune suppression with age.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Proliferation
- Epigenomics
- Forkhead Transcription Factors
- Male
- Methylation
- Mice
- Mice, Inbred C57BL
- Oxidation-Reduction
- T-Lymphocytes, Regulatory
Keywords
- aging
- epigenetics
- methylation
- redox
- regulatory T cell
Aging is associated with low-grade neuroinflammation that includes basal increases in proinflammatory cytokines and expression of inflammatory markers on microglia. Exercise can reduce neuroinflammation following infection in aged animals, but whether exercise modulates basal changes in microglia activation is unknown. Therefore, we evaluated changes in basal microglia activation in cells isolated from the hippocampus and remaining brain following running-wheel access. Adult (4 months) and aged (22 months) male and female BALB/c mice were housed with or without running wheels for 10 weeks. Microglia were isolated from the hippocampus or remaining brain. Flow cytometry was used to determine microglia (CD11b and CD45(low)) that co-labeled with CD86, CD206, and MHC II. Aged mice showed a greater proportion of CD86 and MHC II positive microglia. In aged females, access to a running wheel decreased proportion of CD86 and MHC II microglia in the hippocampus whereas aged males in the running group showed a decrease in the proportion of CD86 microglia in the brain and an increase in the proportion of MHC II microglia in hippocampus and brain. Overall, these data indicate that running-wheel access modulates microglia activation, but these effects vary by age, sex, and brain region.
MeSH Terms
- Aging
- Animals
- Female
- Flow Cytometry
- Hippocampus
- Male
- Mice
- Mice, Inbred BALB C
- Microglia
- Physical Conditioning, Animal
It is well-established that almost all cellular components of innate and adaptive immunity undergo age-related remodelling. The findings on age-related changes in both human and mouse dendritic cells (DCs) are conflicting, whereas there are no data on the influence of aging on rat DCs. In an attempt to fill this gap, freshly isolated splenic DCs expressing CD103 (αOX-62 integrin), a DC specific marker recognized by MRC OX62 monoclonal antibody, from 3- (young) and 26-month-old (aged) Albino Oxford rats were examined for subset composition, expression of activation/differentiation markers (CD80, CD86 and CD40 and MHC II molecules) and endocytic capacity using flow cytometric analysis (FCA). In addition, splenic OX62 DCs cultured in the presence or absence of LPS were analysed for the activation marker and TNF-α, IL-6, IL-12, IL-23, TGF-β1, IL-10 expression using FCA, RT-PCR and ELISA, respectively. Moreover, the allostimulatory capacity of OX62 DCs and IFN-γ, IL-4 and IL-17 production by CD4 T cells in mixed leukocyte reaction was quantified using FCA and ELISA, respectively. It was found that aging: i) shifts the CD4 :CD4- subset ratio in the OX62 DCs population towards the CD4- subset and ii) influences DCs maturation (judging by activation marker expression and efficiency of endocytosis) by affecting the expression of intrinsic (TNF-α and IL-10) and extrinsic maturation regulators. Furthermore, in LPS-matured OX62 DCs from aged rats expression of TNF-α, IL-12, IL-23 and IL-6 was increased, whereas that of IL-10 was diminished compared with the corresponding cells from young rats. Moreover, in MLR, OX62 DCs from aged rats exhibited enhanced Th1/Th17 driving force and diminished allostimulatory capacity compared with those from young rats.
MeSH Terms
- Aging
- Animals
- Culture Media
- Cytokines
- Dendritic Cells
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Rats
- Real-Time Polymerase Chain Reaction
- Spleen
- T-Lymphocytes, Helper-Inducer
Dendritic cells (DC) are central in regulating skin immunity. Immunosenescence is associated with a chronic inflammatory state. Little is known about the contribution of DC to "inflamm-aging". When determining langerhans cell (LC) numbers, we found a 60 % reduction of LC in aged epidermis. Reactive oxygen species(ROS) are linked with aging. The mitochondrial manganese superoxide dismutase (SOD2) is in the first line of antioxidant defense. We investigated the function of DC from SOD2 heterozygous mice (SOD2 /-) and found that at 4 months of age LC numbers are not altered, but activated LC have impaired expression of MHC-II and CD44. Immature SOD2 /- DC produced increased proinflammatory IL-6 and chemokines CXCL1 and CXCL2. Upon challenge SOD2 /- DC accumulated ROS. When activating SOD2 /- DC by LPS they less efficiently upregulated MHC-II, CD86 and CD44. Surprisingly, in vivo contact hypersensitivity (CHS) was enhanced in SOD2 /- mice although SOD2 /- DC were less potent in stimulating wt T cells. However, SOD2 /- T cells showed increased proliferation, even when stimulated with SOD2 /- DC, possibly explaining the increased CHS. Our findings suggest that SOD2 is a molecular candidate in the regulation of "inflamm-aging" conveying both immunosuppressive and proinflammatory signals through alteration of DC and T cell functions.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- B7-2 Antigen
- Cell Differentiation
- Cells, Cultured
- Chemokine CXCL1
- Chemokine CXCL2
- Dendritic Cells
- Dermatitis, Contact
- Heterozygote
- Histocompatibility Antigens Class II
- Humans
- Hyaluronan Receptors
- Inflammation
- Interleukin-6
- Lymphocyte Activation
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Reactive Oxygen Species
- Superoxide Dismutase
- T-Lymphocytes
- Young Adult
Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19( ) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19( ) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19( ) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19( ) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19( ) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19( ) CD24(hi) CD38(hi) cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19( ) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19( ) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Autoimmunity
- B-Lymphocytes
- Cell Differentiation
- Female
- Humans
- Male
- Middle Aged
- Signal Transduction
- Young Adult
Keywords
- B cells
- autoimmunity
- cellular immunology
- inflammation
- rheumatoid factor