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

CD8 T 细胞功能适应慢性病毒的细胞和转录控制

• 批准号: 9160163
• 负责人: WEIGUO CUI
• 金额: $ 41.75万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-16 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160163
• 关键词: Acute; Adopted; Affect; Antigens; Antiviral Agents; Beryllium; Binding; Binding Sites; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell physiology; Chromatin; Chronic; Chronic Phase; Complex; Computer Analysis; Coupled; Data; Deterioration; Development; Effector Cell; Epigenetic Process; Equilibrium; Figs - dietary; Gene Expression; Gene Expression Profile; Genes; Grant; HIV; HIV/HCV; Helper-Inducer T-Lymphocyte; Hepatitis B Virus; Hepatitis C virus; IRF4 gene; Immunotherapy; Infection; Inflammation; Inflammatory; Interleukin-2; Knowledge; Lead; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Mediating; Modeling; Molecular Genetics; Mus; Pathway interactions; Phase; Process; Publishing; Regulatory Element; STAT3 gene; Signal Pathway; Signal Transduction; Source; Stat5 protein; T cell differentiation; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic Effect; Transcriptional Activation; Transcriptional Regulation; Variant; Viral; Viral Antigens; Virus; Virus Diseases; Work; base; cell fate specification; cytokine; exhaust; exhaustion; functional adaptation; immunopathology; improved; insight; meetings; mouse model; novel; pathogen; progenitor; protein complex; receptor; response; transcription factor

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.

慢性病毒感染，例如艾滋病毒和HCV，影响全球数百万的人很难治愈。 慢性病毒的成功放疗在很大程度上取决于健壮的和持久的CD4和CD8 T细胞 反应。尽管病毒特异性CD8 T细胞逐渐降低了其产生效应子细胞因子的能力，并且 面对持续感染（通常称为疲惫），上调抑制性受体PD-1， 几项研究，包括PD-1封锁实现的显着治疗作用，表明 表型“耗尽”的T细胞可以介导至关重要的病原体控制水平。与目前相反 公认的渐进定义观点，我们在这里建议病毒特异性的CD8 T细胞稳定地调整其 谱系规范并进行功能适应，该功能适应已进行了优化以实现一定水平的效应器 功能和病原体控制而不会引起压倒性的免疫病理学。这个新概念进一步 由我们的初步数据支持。我们最近发现了新型的细胞和信号通路， 将CD4衍生的IL-21连接到CD8 T细胞中调节的转录机械的BATF-IRF4-STAT3， 剧烈促进病毒特异性CD8 T细胞中的早期到线相发育过渡。基于 这些新发现，我们假设升高的炎性细胞因子（例如IL-21）和持续 抗原作为慢性病毒感染的标志，通过IL-21-Stat3-Batf和抗原紧密耦合 TCR-IRF4途径，该途径在转录水平上收敛到协作调节基因表达。 支持这一想法，我们的计算分析表明，BATF和IRF4合作与 与晚期效应子特征相关的多个基因的顺式调节元件。有趣的是，很多 这些BATF-IRF4化合物结合元素与STAT3结合位点相邻，这些位点提供了 依赖BATF的STAT3结合和转录激活的结构基础如我们 初步研究。这些共同使我们提出了一个挑衅模型，其中BATF和IRF4形成A 中央监管枢纽调节染色质的可及性和与STAT3的合作以调节中央 控制晚期效应子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）哪个CD4 T细胞的子集提供了“帮助”以维持 CD8 T细胞中的效应函数，（2）是否暂时调节BATF表达和抗原依赖性 在慢性的晚期，CD8效应T细胞分化需要IRF4表达 感染和（3）BATF-IRF4复合物如何与表观遗传水平的Jak-Stats途径合作 会议在晚期效应CD8 T细胞中的独特细胞命令规范。总体而言，这项工作将提供机械 深入了解CD8 T细胞如何整合细胞，分子和遗传信号以稳定调整其 分化过程以满足慢性感染的需求。最终，这项研究获得的知识 可以利用以提高CD8 T细胞在治疗慢性病毒和癌症中的效应子功能。