Regenerative Capacity of Anti-Viral Memory CD8 T cells

 描述（由申请人提供）：CD 8 T细胞在控制病毒、细胞内细菌和原生动物感染中发挥关键作用。急性病毒感染通常会诱导一种强有力的 自我更新的记忆性CD 8 T细胞群体，在感染后持续数十年。对反复感染性损伤的持久保护性免疫取决于维持具有高再生能力的记忆性CD 8 T细胞的干细胞样自我更新群体，即耐受克隆扩增和分化为效应和记忆性CD 8 T细胞的重复循环而不达到衰老的能力。然而，人类衰老与衰老和终末分化的记忆性CD 8 T细胞（效应记忆性CD 45 RA +ve; EMRA）的进行性积累相关，所述记忆性CD 8 T细胞显示出较差的效应子功能和再生能力。调节记忆性CD 8 T细胞的衰老和再生潜力的机制仍然知之甚少。FoxO家族的转录因子减轻衰老并促进干细胞的再生能力。相比之下，肿瘤抑制分子p16 INK 4a促进衰老并限制干细胞的再生潜力。此外，T细胞中的p16 INK 4a表达是衰老的生物标志物，并且终末分化的人T细胞的增殖停滞与升高的p16 INK 4a水平有关。令人兴奋的初步数据表明：（1）FoxO 1在人类衰老EMRA T细胞中的表达显著降低;（2）FoxO 1缺陷导致小鼠记忆性CD 8 T细胞的衰老、再生性下降和p16 INK 4a表达升高。基于这些数据，在具体目标1中，我们将检验“FoxO 1通过抑制p16 INK 4a表达来对抗衰老并促进记忆性CD 8 T细胞的再生潜力”的假设。不仅FoxO 1缺乏，雷帕霉素机制靶点（mTOR）的异常激活也是细胞衰老和老化的显著特征。值得注意的是，FoxO的几种活性忠实地表型复制了T细胞和干细胞中mTOR抑制的作用，这支持了FoxO的功能还包括mTOR拮抗作用的观点。基于FoxO 1消融提高记忆性CD 8 T细胞中mTOR活性的初步数据，在具体目标2中，我们将检验“FoxO 1通过抑制mTOR活性对抗衰老并促进记忆性CD 8 T细胞的保护能力”的假设。这项探索性的R21提案是创新的，因为它试图确定FoxO 1，p16和mTOR之间在控制记忆CD 8 T细胞的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制见解。预测这些对易处理的分子途径的新见解对人类健康具有实质性和广泛的影响，因为我们设想开发治疗性调节FoxO 1-p16/mTOR轴的策略以：（1）恢复老年人的T细胞稳态;（2）增强疫苗诱导的CD 8 T细胞记忆;（3）引发并维持老年人持久的保护性细胞介导的免疫。

 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.