Role of Telomere And Telomerase In Human Lymphocyte Func

Aging

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Abstract

One of the outstanding issues of immunological memory is how memory cells can survive and maintain their replicative capacity over long period of time (whole life time) in vivo. Recent studies indicate that homeostatic cytokines such as IL-7 and IL-15 play essential role in survival and maintenance of memory T cells. IL-7 appears important for the survival of both CD4 and CD8 memory T cells while IL-15 is capable of promoting proliferation and long-term survival of memory CD8 T cells. Although both IL-7 and IL-15 appear to be able to activate telomerase in T cells in short-term culture, their long term effect in regulation of telomerase and telomere length in T cells has not been determined. It is also unclear whether IL-7 and IL-15 regulate telomerase activity differently between naive and memory T cells. To address these questions, we compared IL-7 induced proliferation and telomerase activation between human CD4 naive and memory T cells. We found that more memory CD4 T cells, especially central memory cells, than naive cells underwent cell divisions in response to IL-7, correlating with the levels of IL-7 receptor alpha (IL-7Ra) expression on naive and memory CD4 T cells. Interestingly, although more memory cells divided faster than did naive cells, activated telomerase levels induced by IL-7 were lower in memory cells than in naive cells. The difference of induced telomerase activity between naive and memory cells correlated with the degree of their survival but was not linked to cell division, suggesting that telomerase plays role in T cell survival in homeostasis. We also demonstrated that IL-15 is capable of inducing telomerase activity through activation of Jak3 and PI3-K/AKT signaling pathways in memory CD8 T cells and IL-15 induced telomerase activity is associated with the relative stable telomere length in long term cultured memory CD8 T cells. Unexpectedly, we found that IL-15 could induce down-regulation of CD28 expression in actively proliferating memory CD8 T cells. We further showed the complexity of cytokine network in regulation of CD28 expression and growth of CD28-CD8 T cells. In addition to TNF-alpha, we found that CCL4 (MIP-1beta) had a significant inhibitory effect on the growth of CD28- cells, which in turn down-regulated their expression of CCL4 receptor CCR5. Together, these findings demonstrate that homeostatic cytokines regulate telomerase activity in both CD4 and CD8 as well as naive and memory T cells, and IL-15 and its induced cytokines regulate the generation and growth of CD28-CD8 T cells, suggesting a possible role of IL-15 in the increase in CD28-CD8 T cells that occurs with aging.