Memory T lymphocytes are characterized by their ability to exhibit a rapid response to the recall antigen. Our previous study shows that histone methylation provides a chromatin basis for the rapid transcriptional response of memory CD8 T cells. To understand how the histone methylation patterns are established and maintained in memory T cells, we conducted parallel analyses of gene expression changes with histone methylation changes in nave and memory (central and effector memory cells) CD8 T cells after in vitro stimulation and comparing cells before and after activation-induced cell division. Nave, central memory and effector memory CD8 T cells were isolated from normal adult and stimulated in vitro with antibodies against CD3 and CD28. Gene expression changes were analyzed by microarray and histone methylation (H3K4me3 and H3K27me3) was analyzed by ChIP-Seq. As expected, we observed substantial changes in gene expression (22% increase and 22% decrease of total expressed genes) after 72 hours of stimulation, activation. In parallel, we observed similar trend of histone methylation (H3K4me3 and H3K27me3) changes in corresponding genes in CD8 T cells. Furthermore, we found that the open chromatin of some poised genes in memory CD8 T cells were established in activated nave CD8 T cells, suggesting that activation is a necessary step of convert the memory cell type of chromatin in nave cells. Analysis of gene expression and histone methylation before and after cell division during activation, we found that change of histone H3K4me3 amounts after activation was rather rapid and does not require cell division. Together, these results indicate that histone methylation is dynamic after activation in CD8 T cells without need of cell division, and suggest that activation-induced change of chromatin in nave T cells is part of differentiation process to establish memory T cells. Reduction of T cell receptor (TCR) diversity is believed to occur with age and acts as a major contributor for age-associated decline of immune function. However, neither the actual size of the TCR repertoire nor its precise age-related change have been directly determined. Applying a RACE-PCR-high-throughput sequencing method, we have assessed the TCRβCDR3 repertoire of peripheral blood from 16 adults (21-94 years old) including 7 adults with longitudinal samples. We found that: 1) the size of TCRβCDR3 diversity of CD4+ T cells ranging 1.8 to 2.5 x105;2) the size of TCRβCDR3 diversity was over twice larger in CD4+ than in CD8+ T cells;3) reducing TCRβCDR3 diversity size with age was observed in old adults (>late 60s);and 4) reducing TCRβCDR3 size and altering TCRβCDR3 distribution with age occurred independently in these old adults. These findings reveal for the first time the actual changes of TCRβCDR3 repertoire (reduced diversity and altered distribution) in human adults with age, which could serve as a measure of the immune competency and a guide for the intervention in elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000757-15
Application #
8552466
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2012
Total Cost
$113,477
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Li, Hoi Ming; Hiroi, Toyoko; Zhang, Yongqing et al. (2016) TCRβ repertoire of CD4+ and CD8+ T cells is distinct in richness, distribution, and CDR3 amino acid composition. J Leukoc Biol 99:505-13
Kajimura, Junko; Kyoizumi, Seishi; Kubo, Yoshiko et al. (2016) Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors. Mutat Res Genet Toxicol Environ Mutagen 802:59-65
Cheng, Nai-Lin; Chen, Xiaochun; Kim, Jiewan et al. (2015) MicroRNA-125b modulates inflammatory chemokine CCL4 expression in immune cells and its reduction causes CCL4 increase with age. Aging Cell 14:200-8
Yang, Xinbo; Gao, Mingming; Chen, Guobing et al. (2015) Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope. J Biol Chem 290:29106-19
Slota, Christina; Shi, Alvin; Chen, Guobing et al. (2015) Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation. Brain Behav Immun 46:168-79
Chen, Guobing; Lustig, Ana; Weng, Nan-Ping (2013) T cell aging: a review of the transcriptional changes determined from genome-wide analysis. Front Immunol 4:121
Barber, John S; Yokomizo, Lauren K; Sheikh, Virginia et al. (2013) Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases. Proc Natl Acad Sci U S A 110:8164-9
Chen, Guobing; Weng, Nan-ping (2012) Analyzing the phenotypic and functional complexity of lymphocytes using CyTOF (cytometry by time-of-flight). Cell Mol Immunol 9:322-3
Weng, Nan-ping; Araki, Yasuto; Subedi, Kalpana (2012) The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol 12:306-15
An, Jie; Golech, Susanne; Klaewsongkram, Jettanong et al. (2011) Krüppel-like factor 4 (KLF4) directly regulates proliferation in thymocyte development and IL-17 expression during Th17 differentiation. FASEB J 25:3634-45

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