CCR4
C-C chemokine receptor type 4 (C-C CKR-4) (CC-CKR-4) (CCR-4) (CCR4) (K5-5) (CD194 antigen) [CMKBR4]
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Studies of the mTOR pathway have prompted speculation that diminished mTOR complex-1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long-lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA-KO mice express high levels of two proteins involved in DNA repair, O-6-methylguanine-DNA methyltransferase (MGMT) and N-myc downstream-regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post-transcriptional mechanisms. We show that the CCR4-NOT complex, a post-transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long-lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post-transcriptional regulation involving specific alteration in the CCR4-NOT complex, whose modulation could control multiple aspects of the aging process.
MeSH Terms
- Animals
- Cell Cycle Proteins
- DNA Damage
- DNA Modification Methylases
- DNA Repair Enzymes
- Down-Regulation
- Dwarfism
- Female
- Intracellular Signaling Peptides and Proteins
- Liver
- Longevity
- Male
- Mice, Knockout
- Models, Biological
- Pregnancy-Associated Plasma Protein-A
- RNA, Messenger
- Receptors, CCR4
- Receptors, Somatotropin
- Sirolimus
- TOR Serine-Threonine Kinases
- Transcription Factors
- Tumor Suppressor Proteins
Keywords
IGF
- DNA repair
- gene expression
- molecular biology of aging
- signal transduction
The pathogenic role and frequency of T cell subtypes in early rheumatoid arthritis are still unclear. We therefore performed a comprehensive analysis of the circulating T cell subtype pattern in patients with untreated early rheumatoid arthritis compared to healthy control subjects. Peripheral blood mononuclear cells were obtained from 26 patients with untreated early rheumatoid arthritis and from with 18 age- and sex-matched healthy control subjects. T helper cell types Th0, Th1, Th2, Th17, and Th1/17 and nonclassic T helper subsets were defined by flow cytometry based on the expression of chemokine receptors CCR4, CCR6, and CXCR3. Regulatory T cells were defined by expression of CD25 CD127 and also FOXP3 CXCR5 cells among regulatory and nonregulatory T cells were defined as T follicular regulatory and T follicular helper cells, respectively. The phenotype of T cell subsets was confirmed by transcription factor and cytokine secretion analyses. Multivariate discriminant analysis showed that patients with untreated early rheumatoid arthritis were segregated from healthy control subjects based on the circulating T cell subset profile. Among the discriminator subsets, CCR4 CXCR3 (Th2 and Th17), CTLA4 and FOXP3 subsets were present in significantly higher frequencies, whereas CCR4 (Th1/Th17, CCR6 CCR4 CXCR3 , and Th1) subsets were present in lower frequencies in patients with untreated early rheumatoid arthritis compared with healthy control subjects. The proportions of Th2 and Th17 subsets associated positively with each other and negatively with the CXCR3 /interferon γ-secreting subsets (Th1 and Th1/Th17) in patients with untreated rheumatoid arthritis. The proportions of Th2 cells increased with age in patients with untreated early rheumatoid arthritis and healthy control subjects. The dominance of circulating CCR4 CXCR3 T helper subsets (Th2 and Th17) in untreated early rheumatoid arthritis point toward a pathogenic role of these cells in early stages of the disease.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, Differentiation, T-Lymphocyte
- Arthritis, Rheumatoid
- Case-Control Studies
- Cytokines
- Disease Progression
- Female
- Flow Cytometry
- Gene Expression Profiling
- Humans
- Immunophenotyping
- Lymphocyte Count
- Male
- Middle Aged
- Receptors, CXCR3
- T-Lymphocyte Subsets
- T-Lymphocytes, Helper-Inducer
- T-Lymphocytes, Regulatory
- Transcription Factors
Keywords
- T cell profile
- autoimmunity
- chemokine receptors
- multivariate discriminant analysis
Inflammation and infection are associated with premature birth and with activation of the fetal immune system. We hypothesized that exposure to microbial Toll-like receptor (TLR) ligands plays an important role in neonatal T-cell maturation and that early exposure to microbial products may result in early T-cell maturation and a tendency for these matured effector cells to change their homing receptor patterns. Expression of the CD45RO marker was induced in term neonatal T cells after in vitro exposure to TLR ligands for 7 days. Interestingly, naive T cells from adult blood were unaffected by TLR ligand exposure. In addition, neonatal T cells had more cells with decreased expression of the α4β7 integrins and increased expression of CCR4 after in vitro exposure of TLR ligands-similar to the expression of these molecules in adult naive T cells. These findings are relevant for the understanding of neonatal T-cell maturation and may contribute to our understanding of multiorgan inflammatory complications of prematurity. Cord blood was obtained from term and preterm infants. Using flow cytometry, we identified a mature (CD45RO( )) phenotype in preterm infant cord blood (CB) T cells that had decreased expression of the α4β7 integrins and increased expression of the C-C chemokine receptor 4 (CCR4) as compared with term infant CB.
MeSH Terms
- Adult
- Age Factors
- Aging
- Case-Control Studies
- Cells, Cultured
- Chorioamnionitis
- Female
- Fetal Blood
- Flow Cytometry
- Gestational Age
- Humans
- Immunologic Factors
- Immunologic Memory
- Immunophenotyping
- Infant, Newborn
- Infant, Premature
- Integrins
- Leukocyte Common Antigens
- Ligands
- Lymphocyte Activation
- Phenotype
- Pregnancy
- Premature Birth
- Receptors, CCR4
- Receptors, Lymphocyte Homing
- T-Lymphocytes
- Toll-Like Receptors
- United States
Generalized vitiligo is thought to have an autoimmune etiology and has been correlated with the presence of CD8 T cells specific for melanocyte differentiation Ag. However, limited animal models for the disease have hampered its understanding. Thus, we generated TCR transgenic mice that recognize an epitope of the melanocyte protein, tyrosinase. These animals develop vitiligo with strikingly similar characteristics to the human disease. Vitiligo develops temporally and spatially, with juvenile lesions forming bilaterally in head and facial areas, and only arising later in the body of adult animals. Vitiligo is entirely dependent on CD8 T cells, whereas CD4 T cells exert a negative regulatory effect. Importantly, CD8 T cells can be pervasively present in the skin in the steady state without inducing vitiligo in most areas. This points to developmental differences in melanocyte susceptibility and/or immunological effector mechanisms over time, or in different body locations. Disease is strongly dependent on both IFN-gamma and CXCR3, whereas dependence on CCR5 is more limited, and both CCR4 and perforin are dispensable. Genetic ablation of CXCR3 or IFN-gamma also resulted in scarce CD8 T cell infiltration into the skin. Our results identify unexpected complexity in vitiligo development and point toward possible therapeutic interventions.
MeSH Terms
- Aging
- Animals
- Antigen Presentation
- Autoimmune Diseases
- CD8-Positive T-Lymphocytes
- Disease Models, Animal
- HLA-A Antigens
- HLA-A2 Antigen
- Humans
- Hypopigmentation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Monophenol Monooxygenase
- Receptors, Antigen, T-Cell
- Self Tolerance
- Vitiligo
Mild zinc deficiency is a common condition in healthy elderly individuals leading to impaired cell-mediated immune response. Here we report the effect of improved zinc status on TH1/TH2 balance and on the activation status of T helper cells in 19 healthy elderly subjects aged 69.8 /- 5.1 years. Our investigations revealed a mild zinc deficiency which was adjusted by oral zinc supplementation for seven weeks. Improved serum zinc levels significantly reduced levels of activated T helper cells whereas changes in TH1/TH2 ratio (determined by CCR4 and CCR5 expression) were not observed. These findings suggest that elderly individuals may benefit from moderate zinc supplementation due to improved immune response leading to reduced incidences of autoimmune diseases and infections.
MeSH Terms
- Administration, Oral
- Aged
- Aged, 80 and over
- Aging
- CD4 Antigens
- Dietary Supplements
- Female
- Humans
- Interleukin-2 Receptor alpha Subunit
- Lymphocyte Activation
- Lymphocyte Count
- Male
- Receptors, CCR4
- Receptors, CCR5
- Receptors, Chemokine
- Reference Values
- Th1 Cells
- Th2 Cells
- Zinc
- Zinc Compounds
Killer Ig-like receptors (KIR) are commonly found on human NK cells, gammadelta T cells, and CD8 T cells. Although KIR( ) CD4 T cells are found in certain patients, their prevalence in healthy donors is controversial. We now provide definitive proof that such cells are present in most individuals, and report on their frequency, surface phenotype, cytokine profile, and Ag specificity. The number of KIR( ) CD4 T cells detected in peripheral blood increased with age. In contrast with regular KIR(-) CD4 T cells, the majority of KIR( ) CD4 T cells lacked surface expression of CD27, CD28, CCR4, and CCR7, but did express CD57 and 2B4. In addition, KIR were detected on approximately one-tenth of CD28(-) and CD57( ) memory CD4 T cells. In line with the absence of the Th2 marker CCR4, the KIR( ) CD4 cells produced mainly IFN-gamma and little IL-4, IL-10, or IL-17 upon TCR triggering. Furthermore, the KIR( ) population contained cells that responded to recall Ags in an HLA class II-restricted fashion. Together, our data indicate that KIR-expressing CD4 T cells are predominantly HLA class II-restricted effector memory Th1 cells, and that a significant, previously unrecognized fraction of effector memory Th1 cells expresses KIR.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- CD4 Lymphocyte Count
- CD4-Positive T-Lymphocytes
- Cell Membrane
- Clone Cells
- Epitopes, T-Lymphocyte
- Fetal Blood
- Gene Expression Profiling
- Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
- HLA-D Antigens
- Humans
- Immunologic Memory
- Immunophenotyping
- Mice
- Mice, Transgenic
- Middle Aged
- Molecular Sequence Data
- Receptors, Immunologic
- Receptors, KIR
- Th1 Cells
In humans and rodents a population of naturally occurring CD4( )CD25( ) T cells are suppressor T (CD25( ) Ts) cells, which are considered to maintain peripheral immunological tolerance. Recently, we have described a unique chemotactic response profile for human CD25( ) Ts cells, but their homing potential remains poorly defined. Here, we document a heterogeneous homing potential of human peripheral blood CD25( ) Ts cells consistent with their ability to mediate immunosuppression at distinct locations. Surprisingly, CD25( )Ts cells are depleted of gut-homing integrin alpha(4) ( )beta(7) ( ) T cells, while being enriched in skin-homing cutaneous lymphocyte antigen (CLA)( ) T cells. These findings document heterogeneous homing potential of peripheral blood-borne CD25( ) Ts cells with marked skewing for skin- versus gut-homing. Expression of CCR4 associates with both CD25 and CLA cell surface markers, being highest on CD4( )CLA( )CD25( ) T cells. Importantly, CD4( )CD25( ) Ts cells isolated from human cord blood lack expression of CLA while expressing CCR4, suggesting intrinsic expression of CCR4 on CD25( ) Ts cells. These observations indicate that the increased expression of CCR4, which is proposed to guide CD25( ) Ts cells to DC, is an intrinsic feature of CD25( ) Ts cells.
MeSH Terms
- Adult
- Aging
- Antigens, Differentiation, T-Lymphocyte
- Antigens, Neoplasm
- Blood
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Cell Adhesion
- Chemokine CCL17
- Chemokine CCL22
- Chemokines, CC
- Chemotaxis, Leukocyte
- Fetal Blood
- Gene Expression Regulation
- Humans
- Immune Tolerance
- Immunophenotyping
- Infant, Newborn
- Integrins
- Intestines
- Membrane Glycoproteins
- Organ Specificity
- Receptors, CCR4
- Receptors, Chemokine
- Receptors, Interleukin-2
- Receptors, Lymphocyte Homing
- Skin
- T-Lymphocyte Subsets
- T-Lymphocytes, Regulatory
Intracisternal A-particle (IAP) sequences are endogenous retrovirus-like elements present at 1,000 copies in the mouse genome. We had previously identified IAP-related transcripts of unusual size (6 and 10 kilobases (kb)), which are observed exclusively in the liver of the aging mouse. In this report, using cDNA libraries that we have constructed from the liver mRNAs of an aged DBA/2 mouse, we have cloned and entirely sequenced the corresponding cDNAs. Both are initiated within the 5' long terminal repeat of a type IDelta1 IAP sequence, and correspond to a read-through into a unique flanking cellular sequence containing a 966-nucleotide open reading frame, located 3' to the IAP sequence. The 6-kb IAP-related transcript corresponds to a post-transcriptional modification of the 10-kb mRNA, and is generated by a splicing event with the donor site in the IAP sequence, and the acceptor site 5' to the open reading frame. This open reading frame is located on chromosome 3, is evolutionarily conserved, and discloses significant similarity to the yeast CCR4 transcription factor at the amino acid level. The specific expression of these age-induced transcripts, which account for more than 50% of the IAP-related transcripts in the liver of old mice, is therefore entirely consistent with the induction of a single genomic locus, thus strengthening the importance of position effects for the expression of transposable elements. Characterization of this locus should now allow studies on its chromatin and methylation status, and on the "molecular factors of senescence" possibly involved in its induction.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- Blotting, Northern
- Chimera
- Chromosome Banding
- DNA, Complementary
- DNA-Binding Proteins
- Fungal Proteins
- Genes, Intracisternal A-Particle
- Liver
- Mice
- Molecular Sequence Data
- Open Reading Frames
- Ribonucleases
- Saccharomyces cerevisiae Proteins
- Sequence Alignment
- Transcription Factors
- Transcription, Genetic
- Zinc Fingers