The Cellular and Transcriptional Control of CD8 T Cell Functional Adaptation to Chronic Viruses

影响全球数百万人的艾滋病毒和丙型肝炎等慢性病毒感染很难治愈。 成功根除慢性病毒在很大程度上取决于强大和持久的CD4和CD8T细胞 回应。尽管病毒特异性CD8T细胞逐渐降低其产生效应性细胞因子和 在持续感染(通常称为衰竭)时上调抑制受体PD-1， 几项研究，包括PD-1阻断取得的显著治疗效果，表明 表型上“耗尽”的T细胞可以调节病原体控制的关键水平。与目前形成对比的是 公认的进行性恶化的观点，我们在这里提出，病毒特异性CD8T细胞稳定地调整其 血统规范，并经历功能适应，这是优化以满足一定级别的效应器 功能和病原体控制，而不会导致压倒性的免疫病理。这一新概念更进一步 由我们的初步数据支持。我们最近发现，新的细胞和信号通路，其中 将CD4来源的IL-21与BATF-IRF4-STAT3调节的CD8T细胞转录机制连接起来， 大力促进病毒特异性CD8 T细胞由早向晚的发育转变。基于 这些新发现，我们假设升高的炎性细胞因子(如IL-21)和持续性 作为慢性病毒感染标志的抗原通过IL-21-STAT3-BATF和抗原-BATF紧密偶联。 TCR-IRF4通路，这些通路在转录水平上聚合，共同调节基因的表达。 支持这一观点，我们的计算分析表明，BATF和IRF4协同结合到 与晚期效应信号相关的多个基因的顺式调控元件。有趣的是，许多人 在这些BATF-IRF4化合物结合元件中，与STAT3结合位点相邻，从而提供 BATF依赖的STAT3结合和转录激活的结构基础 初步研究。总之，我们提出了一个挑衅性的模式，在这个模式中，BATF和IRF4形成了一个 中央调控中心调节染色质的可及性，并与STAT3合作调节中央 调控晚期效应分子CD8 T细胞分化和功能的转录网络。在这笔赠款中， 我们将使用最先进的技术来阐明(1)哪一种CD4T细胞亚群对维持 CD8T细胞的效应器功能，(2)是否在时间上调节BATF的表达和抗原依赖 慢性粒细胞白血病晚期CD8效应T细胞分化需要IRF4的协同表达 感染，以及(3)BATF-IRF4复合体如何在表观遗传水平上与JAK-STATS途径合作 在迟效CD8T细胞中赋予不同的细胞命运规范。总体而言，这项工作将提供机械性 对CD8 T细胞如何整合细胞、分子和遗传信号以稳定地调节它们的 分化过程中满足慢性感染的需要。最终，从这项研究中获得的知识 可以用来改善CD8 T细胞在治疗慢性病毒和癌症方面的效应功能。

Chronic viral infections such as HIV and HCV affecting millions of people globally are difficult to cure. Successful eradication of chronic viruses greatly depends on robust and long-lasting CD4 and CD8 T cell responses. Although virus-specific CD8 T cells gradually reduce their ability to produce effector cytokines and upregulate inhibitory receptor PD-1 in the face of persistent infection (commonly referred to as exhaustion), several studies, including the remarkable therapeutic effects achieved by PD-1 blockade, suggest that phenotypically “exhausted” T cells can mediate a crucial level of pathogen control. In contrast to the presently accepted view of progressive deterioration, we propose here that virus-specific CD8 T cells stably adjust their lineage specification and undergo a functional adaptation, which is optimized to fulfill a certain level of effector function and pathogen control without causing overwhelming immunopathology. This new concept is further supported by our preliminary data. We have recently found that novel cellular and signaling pathways, which connect CD4-derived IL-21 to BATF-IRF4-STAT3 regulated transcriptional machinery in CD8 T cells, vigorously promote the early-to-late phase developmental transition in virus-specific CD8 T cells. Based on these new findings, we hypothesize that elevated inflammatory cytokines (such as IL-21) and persistent antigen as hallmarks of chronic viral infection are tightly coupled through IL-21-STAT3-BATF and Antigen- TCR-IRF4 pathways, which converge on a transcriptional level to collaboratively regulate gene expression. Supporting this idea, our computational analyses have revealed that BATF and IRF4 cooperatively bind to the cis-regulatory elements of multiple genes associated with the late phase effector signatures. Intriguingly, many of these BATF-IRF4 compound-binding elements are adjacent to STAT3 binding sites, which provide the structural basis of BATF-dependent STAT3 binding and transcriptional activation as evidenced in our preliminary studies. Together, these lead us to propose a provocative model, in which BATF and IRF4 form a central regulatory hub to modulate chromatin accessibility and cooperate with STAT3 to regulate the central transcriptional networks that govern the late phase effector CD8 T cell differentiation and function. In this grant, we will use state-of-the-art techniques to elucidate (1) which subset of CD4 T cells provides “help” to sustain the effector function in CD8 T cells, (2) whether temporally regulated BATF expression and antigen dependent IRF4 expression are cooperatively required for CD8 effector T cell differentiation at the late phase of chronic infection, and (3) how BATF-IRF4 complex cooperates with JAK-STATs pathways on the epigenetic level to confer a distinct cell-fate specification in late effector CD8 T cells. Overall, this work will provide mechanistic insights into how CD8 T cells integrate the cellular, molecular and genetic signals to stably adjust their differentiation process to meet the needs of chronic infection. Ultimately, knowledge gained from this study could be harnessed to improve the effector function of CD8 T cells in treating chronic viruses and cancer.