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

基本信息

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
项目类别：
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

项目摘要

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.

影响全球数百万人的艾滋病毒和丙肝病毒等慢性病毒感染很难治愈。成功根除慢性病毒很大程度上取决于强大且持久的 CD4 和 CD8 T 细胞尽管病毒特异性 CD8 T 细胞逐渐降低其产生效应细胞因子和细胞因子的能力。面对持续感染（通常称为衰竭）时上调抑制性受体 PD-1，多项研究，包括 PD-1 阻断所取得的显着治疗效果，表明与目前相比，表型“耗尽”的 T 细胞可以介导关键水平的病原体控制。鉴于渐进性恶化的公认观点，我们在此提出病毒特异性 CD8 T 细胞可以稳定地调整其谱系规范并进行功能适应，经过优化以满足一定水平的效应器功能和病原体控制而不引起压倒性的免疫病理学进一步推动了这一新概念。我们最近发现了新的细胞和信号传导途径，这得到了我们的初步数据的支持。将 CD4 衍生的 IL-21 连接到 CD8 T 细胞中 BATF-IRF4-STAT3 调节的转录机制，大力促进病毒特异性CD8 T细胞早期到晚期的发育转变。这些新发现表明，炎症细胞因子（如 IL-21）的升高和持续存在作为慢性病毒感染标志的抗原通过 IL-21-STAT3-BATF 和抗原紧密耦合 TCR-IRF4 通路在转录水平上汇聚以协同调节基因表达。支持这一观点的是，我们的计算分析表明 BATF 和 IRF4 协同结合有趣的是，许多基因的顺式调控元件与后期效应特征相关。这些 BATF-IRF4 化合物结合元件与 STAT3 结合位点相邻，这提供了 BATF 依赖性 STAT3 结合和转录激活的结构基础，如我们的研究中所证明的这些初步研究共同引导我们提出了一个具有挑战性的模型，其中 BATF 和 IRF4 形成了一个模型。中枢调节染色质可及性并与STAT3配合调节中枢控制晚期效应 CD8 T 细胞分化和功能的转录网络。我们将使用最先进的技术来阐明 (1) CD4 T 细胞的哪一个子集提供“帮助”来维持 CD8 T 细胞中的效应器功能，(2) 是否暂时调节 BATF 表达和抗原依赖性 IRF4 表达是慢性疾病晚期 CD8 效应 T 细胞分化所必需的。感染，以及（3）BATF-IRF4复合物如何在表观遗传水平上与JAK-STATs通路合作总体而言，这项工作将提供晚期效应 CD8 T 细胞的独特细胞命运规范。深入了解 CD8 T 细胞如何整合细胞、分子和遗传信号以稳定地调整其最终，从这项研究中获得的知识可以满足慢性感染的分化过程。可用于改善 CD8 T 细胞治疗慢性病毒和癌症的效应功能。