Regenerative Capacity of Anti-Viral Memory CD8 T cells

 描述(申请人提供)：CD8 T细胞在控制病毒、细胞内细菌和原生动物感染方面发挥关键作用。急性病毒感染通常会诱导一种有效的 在感染后持续数十年的记忆CD8 T细胞的自我更新群体。对反复感染性损伤的持久保护性免疫依赖于具有高再生能力的干细胞样记忆CD8 T细胞的自我更新群体的维持，即在不衰老的情况下耐受克隆扩增和分化为效应和记忆CD8 T细胞的重复周期的能力。然而，人类衰老与衰老和终末分化的记忆CD8 T细胞(效应记忆CD45RA ve；EMRA)的逐渐积累有关，这些细胞表现出较差的效应功能和再生能力。调节记忆性CD8T细胞衰老和再生能力的机制仍然知之甚少。FoxO转录因子家族可以减缓干细胞的衰老并促进其再生能力。相比之下，肿瘤抑制分子p16INK4a促进衰老，限制干细胞的再生潜力。此外，T细胞中p16INK4a的表达是衰老的生物标志物，人类终末分化的T细胞增殖停滞与p16INK4a水平升高有关。令人兴奋的初步数据显示：(1)FoxO1在衰老的人EMRA T细胞中的表达显著降低；(2)FoxO1缺乏导致小鼠衰老、记忆CD8 T细胞再生能力下降和p16INK4a表达上调。基于这些数据，在特定的目标1中，我们将检验“FoxO1通过抑制p16INK4a的表达来对抗衰老并促进记忆性CD8 T细胞的再生能力”的假设。不仅FoxO1缺乏，雷帕霉素机制靶点(MTOR)的异常激活也是细胞衰老的一个显著特征。值得注意的是，FOXO的几种活性在T细胞和干细胞中忠实地复制了mTOR抑制的作用，这支持了FoxO的功能也包括对mTOR的拮抗的观点。基于FoxO1抑制记忆性CD8 T细胞mTOR活性的初步数据，在特定的目标2中，我们将验证“FoxO1通过抑制mTOR活性来对抗衰老，提高记忆性CD8 T细胞的保护能力”的假说。这一探索性的R21方案具有创新性，因为它试图确定FoxO1、p16和mTOR之间在调控记忆CD8 T细胞再生潜力方面的新联系，并为老年人记忆T细胞的失调状态和再生衰退提供机械性见解。这些对易于处理的分子通路的新见解预计将对人类健康产生实质性和广泛的影响，因为我们预见到通过治疗调节FoxO1-p16/mTOR轴的策略的开发：(1)恢复老年人的T细胞稳态；(2)增强疫苗诱导的CD8 T细胞记忆；(3)在老年人中诱导和维持持久的保护性细胞介导免疫。

 DESCRIPTION (provided by applicant): CD8 T cells play crucial roles in control of infections with viruses, intracellular bacteria and protozoa. Acute viral infections typically induce a potent self-renewing population of memory CD8 T cells that persists for decades after infection. Durable protective immunity to repeated infectious insults depends upon the maintenance of a stem-cell-like self-renewing population of memory CD8 T cells with high regenerative capacity i.e. the competence to endure repeated cycles of clonal expansion and differentiation into effector and memory CD8 T cells without attaining senescence. However, human aging is associated with the progressive accumulation of senescent and terminally differentiated memory CD8 T cells (effector memory CD45RA+ve; EMRA) that display poor effector functions and regenerative capacity. The mechanisms that regulate the senescence and regenerative potential of memory CD8 T cells remain poorly understood. The FoxO family of transcription factors mitigates senescence and promotes the regenerative capacity of stem cells. By contrast, the tumor suppressor molecule p16INK4a promotes senescence and limits the regenerative potential of stem cells. Further, p16INK4a expression in T cells is a biomarker of aging, and proliferative arrest of terminally differentiated human T cells is linked to elevated p16INK4a levels. Exciting preliminary data show that: (1) FoxO1 expression is markedly reduced in human senescent EMRA T cells; (2) FoxO1 deficiency results in senescence, regenerative decline of memory CD8 T cells and elevated expression of p16INK4a in mice. Based on these data, in specific aim 1, we will test the hypothesis that "FoxO1 opposes senescence and promotes the regenerative potential of memory CD8 T cells by repressing p16INK4a expression". Not only FoxO1 deficiency, aberrant activation of the mechanistic target of rapamycin (mTOR) is also a prominent feature of cellular senescence and aging. Remarkably, several activities of FoxOs faithfully phenocopy the effects of mTOR inhibition in T cells and stem cells, which supports the idea that the functions of FoxO also include antagonism of mTOR. Based on preliminary data that FoxO1 ablation elevated mTOR activity in memory CD8 T cells, in specific aim 2, we will test the hypothesis that "FoxO1 opposes senescence and promotes the protective capacity of memory CD8 T cells by restraining mTOR activity". This exploratory R21 proposal is innovative because, it seeks to identify a new link between FoxO1, p16 and mTOR in governing the regenerative potential of memory CD8 T cells, and provide mechanistic insights into the dysregulated state and regenerative decline of memory T cells in the elderly. Such new insights into the tractable molecular pathways are predicted to have a substantive and broad impact on human health because, we envision development of strategies to therapeutically modulate the FoxO1-p16/mTOR axis to: (1) restore T-cell homeostasis in the elderly; (2) enhance vaccine-induced CD8 T cell memory; (3) elicit and maintain durable protective cell-mediated immunity in the elderly.