Role of Telomere and telomerase In Human Lymphocyte Function and Aging

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Cytomegalovirus (CMV) infection leads to effector memory CD8+ T cell expansion, shortened telomere length, and is associated with immune dysfunction in old humans. However, the molecular alterations of CMV-specific CD8+ T cells in CMV infected healthy young and middle-aged adults has not been fully understood. We compared CD8+ T cells specific for a CMV epitope (pp65495-503) and an influenza A virus (IAV) epitope (M158-66) from the same healthy adults with serum positive for anti-CMV IgG. Compared to the IAV-specific CD8+ T cells, CMV-specific CD8+ T cells were more differentiated and had a reduced activation-induced expansion in vitro, particularly central memory (TCM) but not nave (TN) cells. Furthermore, we found that CD70 expression was reduced in CMV-specific CD28+CD8+ TCM and that CD70+ TCM had better expansion in vitro than did CD70- TCM. Mechanistically, we demonstrated that CD70 directly enhanced MAPK phosphorylation and CMV-specific CD8+ TCM cells reduced MAPK signaling upon activation. Lastly, we showed that age did not exacerbate reduced CD70 expression in CMV- specific CD8+ TCM cells. Our findings demonstrated that CMV infection causes mild CD8+ T cell expansion, reduced CD70 expression and signaling, and proliferation of CMV-specific CD28+CD8+ TCM cells in young and middle-aged healthy adults and revealed an age-independent and CMV infection-specific impact on CD8+ memory T cells. Telomere length records past cell divisions and predicts the cellular replicative potential. The underlying mechanisms of short telomere-induced cell senescence are largely supported by culture cells and genetically modified mouse models. The cell cycle is a tightly controlled process. CDKN2a (p16) and CDKN1a (p21) are key regulators of cell cycle progression, and their expressions significantly increase in human T cells with age. However, it is not fully understood how shorter telomeres in a T cell triggers cessation of cell cycle or what regulates p16 or p21 expressions in shorter telomere T cells. Lack of functional measurement of short telomere lymphocytes impedes the precise interpreting of the roles of the telomere, p16, and p21 in T cells. Here we plan to use a new method we developed to measure telomere length and p16 and p21 levels in individual T cells, apply scRNAseq to identify gene expression changes in p16/p21 expressing T cells, and test the proliferation limit of T cells with short telomere in Tert KO/p16 or p21 reporter mice. Our study will provide evidence of the functional changes in short telomere, p16 and p21 expressing T cells and may explain telomere in T cell function, cellular senescence, and aging.