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

影响全球数百万人的慢性病毒感染，如艾滋病毒和丙型肝炎病毒，很难治愈。 慢性病毒的成功根除在很大程度上取决于强大和持久的CD 4和CD 8 T细胞 应答尽管病毒特异性CD 8 T细胞逐渐降低其产生效应细胞因子的能力， 在面对持续感染时上调抑制性受体PD-1（通常称为衰竭）， 一些研究，包括PD-1阻断所达到的显著治疗效果，表明， 表型上“耗尽”的T细胞可以介导关键水平的病原体控制。与目前相比， 我们在此提出，病毒特异性CD 8 T细胞稳定地调节其免疫功能， 谱系特化并经历功能适应，其被优化以满足一定水平的效应子。 功能和病原体控制，而不会引起压倒性的免疫病理学。这一新概念进一步 我们的初步数据支持。我们最近发现，新的细胞和信号通路， 将CD 4-衍生的IL-21连接到CD 8 T细胞中的BATF-IRF 4-STAT 3调节的转录机器， 有力地促进病毒特异性CD 8 T细胞从早期到晚期的发育转变。基于 这些新的发现，我们假设升高的炎症细胞因子（如IL-21）和持续的 作为慢性病毒感染标志的抗原通过IL-21-STAT 3-BATF和抗原- TCR-IRF 4通路，其在转录水平上会聚以协同调节基因表达。 支持这一观点，我们的计算分析显示，BATF和IRF 4协同结合到 与晚期效应物标签相关的多个基因的顺式调节元件。有趣的是，许多 这些BATF-IRF 4化合物结合元件中的至少一个与STAT 3结合位点相邻，所述STAT 3结合位点提供了与所述化合物结合的结合位点。 BATF依赖性STAT 3结合和转录激活的结构基础，如我们在 初步研究。总之，这些导致我们提出一个挑衅性的模型，其中BATF和IRF 4形成一个 调节染色质可及性的中央调节枢纽，并与STAT 3合作调节中央调节中心， 这些转录网络控制晚期效应CD 8 T细胞分化和功能。在这份补助金中， 我们将使用最先进的技术来阐明（1）CD 4 T细胞的哪一个亚群提供“帮助”维持 CD 8 T细胞中的效应子功能，（2）是否暂时调节BATF表达和抗原依赖性 IRF 4表达是慢性淋巴细胞白血病晚期CD 8效应T细胞分化所需的协同作用。 感染，以及（3）BATF-IRF 4复合物如何在表观遗传水平上与JAK-STAT通路合作， 在晚期效应CD 8 T细胞中赋予不同的细胞命运特化。总的来说，这项工作将提供机械 深入了解CD 8 T细胞如何整合细胞，分子和遗传信号，以稳定地调节其 分化过程，以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CD 8 T细胞在治疗慢性病毒和癌症中的效应功能。

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.