Regulation of T cell immunity by the cytosolic RIG-I like receptors

胞质 RIG-I 样受体对 T 细胞免疫的调节

• 批准号: 8897470
• 负责人: Mehul Shamal Suthar
• 金额: $ 44.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897470
• 关键词: Adaptor Signaling Protein; Antigen Presentation; Antiviral Agents; Apoptosis; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Caspase; Cell Survival; Cell surface; Cessation of life; Clonal Expansion; Culicidae; Cytokine Signaling; Dendritic Cells; Dendritic cell activation; Effector Cell; Flavivirus; Flavivirus Infections; Gene Expression; Health; Human; Immune; Immune response; Immunity; Infection; Inflammatory; Integration Host Factors; Interferon Type I; Interferons; Mediating; Memory; Mitochondria; Mitochondrial Proteins; Natural Immunity; Pathway interactions; Pattern recognition receptor; Peripheral; Play; Process; Public Health; RNA Helicase; Receptor Activation; Receptor Signaling; Regulation; Role; Signal Transduction; Spleen; T cell regulation; T cell response; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Vaccination; Vaccines; Viral; Virus Diseases; Virus Replication; West Nile virus; cytokine; defined contribution; insight; lymph nodes; neurotropic; new therapeutic target; novel; pathogen; programs; receptor; receptor function; response; sensor; viral RNA

DESCRIPTION (provided by applicant): Dendritic cells are critical for regulating T cell immune responses during virus infection. DCs provide the three necessary signals for optimal T cell activation, which include antigen presentation (signal 1), co-stimulation (signal 2), and inflammatory cytokines (signal 3). In turn, this leads to rapid T cell proliferation, clonal expansion, differentiation into effector cells, and formation of memory T cells, that combined, are critical for effective pathogen clearance and protection against re-infection. Type I interfero, regulated by the innate immune sensors of viral infection, play a key role in activation of innate and adaptive immune responses during virus infection. However, it is not clear how innate immune sensing regulates protective T cell immune responses during virus infection. We study West Nile virus (WNV) infection, a neurotropic mosquito-borne flavivirus of significant public health concern throughout the world, to dissect the viral and host factors that govern immunity to infection. Following WNV infection of DCs, the RLRs induce a robust type I interferon- mediated antiviral innate immune response that is critical for controlling virus replication. We recently discovered that the RLR LGP2, which lacks the critical caspase-activation and recruitment domains required for innate immune signaling, was found to function in a T cell-intrinsic manner to promote CD8+ T cell survival and effector functions. The absence of LGP2 in CD8+ T cells led to enhanced cell surface expression of death receptors, activation of extrinsic apoptosis signaling, and reduced cytokine secretion. Surprisingly, the protein mitochondrial antiviral signaling (MAVS), which is the essential adaptor to RLR signaling and a known binding partner of LGP2, was not required for promoting T cell survival. These findings demonstrate that LGP2 functions in a MAVS-independent manner to promote T cell immunity. Our studies have defined a key role for the RLRs at the interface between innate (DCs) and adaptive (T cells) immunity during virus infection. However, the mechanism underlying RLR regulation of T cell immunity is not well understood. In this proposal, we will evaluate two specific hypotheses: (1) The RLRs' function within DCs to regulate activation, function, and T cell priming during WNV infection; and (2) LGP2 functions within CD4+ and CD8+ T cells to regulate protective effector and memory immune responses during WNV infection. These proposed studies will likely reveal a broader role for the RLRs as well as uncover new pathways by which host RNA helicases regulate immunity during virus infection. This proposal likely will reveal new therapeutic targets and strategies for vaccine protection against flavivirus infection.

描述（由申请人提供）：树突状细胞对于调节病毒感染过程中T细胞免疫反应至关重要。 DC提供了最佳T细胞激活的三个必要信号，其中包括抗原表现（信号1），共刺激（信号2）和炎症细胞因子（信号3）。反过来，这会导致T细胞快速增殖，克隆扩张，分化为效应细胞以及组合的记忆T细胞的形成对于有效的病原体清除和防止再感染至关重要。 I型干扰素受病毒感染的先天免疫传感器调节，在病毒感染过程中的先天和适应性免疫反应激活中起关键作用。但是，尚不清楚先天免疫感如何调节病毒感染过程中保护性T细胞免疫反应。我们研究了西尼罗河病毒（WNV）感染，这是全世界对公共卫生关注的重要公共卫生关注的神经蚊子传播的，以剖析控制感染免疫的病毒和宿主因素。 DC的WNV感染后，RLR诱导了稳健的I型干扰素介导的抗病毒先天免疫反应，这对于控制病毒复制至关重要。我们最近发现，缺乏先天免疫信号传导所需的临界caspase激活和募集域的RLR LGP2被发现以T细胞内的方式起作用，以促进CD8+ T细胞存活和效应子功能。 CD8+ T细胞中没有LGP2导致死亡受体的细胞表面表达增强，外在凋亡信号传导的激活以及细胞因子分泌减少。令人惊讶的是，蛋白质线粒体抗病毒信号传导（MAV）是RLR信号传导的必不可少的适配器，也是LGP2的已知结合伴侣，并不需要促进T细胞存活。这些发现表明，LGP2以非依赖性的方式起作用以促进T细胞免疫。我们的研究定义了在病毒感染期间先天（DC）和适应性（T细胞）免疫力之间接口处的RLR的关键作用。但是，尚不清楚T细胞免疫的RLR调节的基础机制。在此提案中，我们将评估两个特定的假设：（1）在WNV感染过程中，DC中的RLR功能调节激活，功能和T细胞启动； （2）LGP2在CD4+和CD8+ T细胞中的功能可调节WNV感染期间的保护效应子和记忆免疫反应。这些提出的研究可能会揭示RLR的更广泛作用，并发现新的途径，宿主RNA解旋酶在病毒感染过程中调节免疫力。该提案可能会揭示新的治疗靶标和策略，以防止疫苗保护侵害黄病毒感染。