Lymphocyte Differentiation Section
Nan-ping Weng, M.D., Ph.D., Senior Investigator
The adaptive immune system plays an essential role in protecting the body against external infectious agents such as virus, bacteria, and other microorganisms and internal cancerous cells. The function of adaptive immunity declines with age, which contributes to increased morbidity and mortality in the older population. Understanding how age-associated decline of immune function is the overall mission of NIA. Our past work has contributed to the identifying some of the key age-associated changes in the adaptive immune system, including alteration of lymphocyte composition, shortened telomere lengths and its relationship with age-changes in inflammatory cytokines and CMV IgG titers, and reduced telomerase expression in both CD4+ and CD8+ T cells with age. But the molecular mechanisms underlying the overall age-associated changes in T cells and their relative contributions to the decline of T cell function have not been adequately addressed. The research interest of my laboratory is to elucidate the molecular mechanisms of T cell differentiation, function, and their changes with age. We focus on three specific aspects: 1) general and antigen-specific T cell receptor (TCR) repertoires and their change with age; 2) transcriptional and epigenetic changes in CD8+ T cells with age and their consequences; and 3) regulation of lymphocyte replicative lifespan via telomere and telomerase.
Immunological memory and immune receptor specificity are two defining features of adaptive immunity. In T cells, a diverse TCR repertoire is essential to ensure the protection from all potential intruders throughout the lifespan. Recent studies suggest that smaller TCRb repertoire in the elderly than in young subjects, but the precise changes of TCR in size and in content with age is not known. We conducted a longitudinal study with an improved method and examined the age influences on both CD4+ and CD8+ T cells and their subsets. Our findings provide detailed age changes of TCRa and TCRb repertoires at specific T cell subsets and reveal age-impact on different subset of T cells.
Alteration of transcriptome and epigenetic landscapes in CD8+ T cells have recently been reported (8-16). These studies are based on average changes in gene expression and epigenetic markers and detect most prominent changes in a population but not those subtle changes. It is also unclear whether these observed changes occur in limited subsets of cells or in all cells. We used single cell RNAseq (scRNAseq) and multicolor flow cytometry methods and analyzed transcriptome and protein changes of human CD8+ T cells with both longitudinal and cross-sectional samples spanning nine decades of life. Our scRNAseq and flow cytometry studies identified 11 subpopulations of CD8+ T cells, their changes in proportion and their common changes in expressed genes with age. We unraveled three distinct modes of the alteration of gene expressions: 1) percentage of expressing cells, 2) level in expressing cells and 3) both. Lastly, the transcriptome changes in CD8+ T cells were correlated with the cumulation of mutation in cells and were used to predict individual cell age.
Telomeres are special structures of chromosomal ends and telomerase is an essential enzyme for the synthesis of telomeres, and they play an essential role in the regulation of cellular replicative lifespan. Telomere attrition occurs in lymphocytes with age and critically shortened telomeres cause cessation of cell division in vitro. However, it is less known if telomere attrition plays any role in age-associated decline of immune function in vivo in humans nor how age-influence expression of telomerase. Our longitudinal studies revealed that age-related trajectories of telomere attrition, elevated circulating inflammatory cytokines, and anti-CMV IgG are independent, and that aging individuals do not show a uniform pattern of change in these variables. Telomerase expression reduces with T cell differentiation and aging. Together, immune aging processes are complex and vary across individuals, and the use of multiple biomarkers is essential to evaluation of biological aging of the immune system.
• General and antigen-specific TCR repertoires: diversity, distribution, and age-associated changes
• Transcriptome and epigenetic features of CD8+ T cells and their changes with age
• Roles of telomere and telomerase in human immune function
Findings and Publications
Chen, G, Yang, XB, Ko, A, Gao, MM, Sun,X, Shi, A, Zhang,Y, Mariuzza, R, and Weng, N-P Sequence and structural analyses reveal distinct and highly diverse human CD8+ TCR repertoires to immunodominant viral antigens. Cell Reports 19(3):569-583 2017 PubMed Central PMCID: PMC5472051.
Lustig A, Liu H, Metter J, Yang A, Resnick S, Ferrucci L, Hodes RJ, and Weng NP. Distinct and independent age-associated trajectories in telomere attrition and elevating circulating inflammatory cytokines in human individuals in vivo. Frontiers in Immunology 7(26):38988, 2017. PubMed Central PMCID: PMC5472051.
Chen G, Subedi K Chakraborty S, Sharov A, Lu J, Mi X, Wersto R, Sung M, and Weng NP. Ezh2 regulates activation-induced CD8+ T cell cycle progression via repressing Cdkn2a and Cdkn1c expression. Frontiers in Immunology 9:549, 26 2018. PubMed Central PMCID: PMC5879148.
Patrick MS, Cheng NL, Kim J, An J, Dong F, Yang Q, Zou I, and Weng NP. Human T cell differentiation negatively regulates telomerase expression resulting in reduced activation-induced cell proliferation and survival. Frontiers in Immunology 10:1993 2019 PubMed Central PMCID: PMC6712505.
Ko A, Watanabe M, Nguyen T, Shi A, Achour A, Zhang B, Sun X, Wang Q, Zhuang Y, Weng NP and Hodes RJ. TCR repertoires of thymic conventional and regulatory T cells: Identification and characterization of both unique and shared TCR sequences. J Immunol 204:858-867, 2020 PubMed Central PMCID: PMC7002224