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（由申请方提供）：树突状细胞对于病毒感染期间调节T细胞免疫应答至关重要。DC为最佳T细胞活化提供三种必要的信号，包括抗原呈递（信号1）、共刺激（信号2）和炎性细胞因子（信号3）。反过来，这导致快速T细胞增殖、克隆扩增、分化成效应细胞和记忆T细胞的形成，其组合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感受器调节，在病毒感染期间激活先天和适应性免疫应答中起关键作用。然而，目前尚不清楚先天免疫传感如何在病毒感染期间调节保护性T细胞免疫应答。我们研究西尼罗河病毒（WNV）感染，一种嗜神经性蚊媒黄病毒的重大公共卫生问题在世界各地，解剖病毒和宿主因素，管理免疫感染。在DC的WNV感染后，RLR诱导稳健的I型干扰素介导的抗病毒先天免疫应答，其对于控制病毒复制是关键的。我们最近发现，缺乏先天免疫信号传导所需的关键半胱天冬酶激活和募集结构域的RLR LGP 2被发现以T细胞内在方式发挥作用，以促进CD 8 + T细胞存活和效应子功能。CD 8 + T细胞中LGP 2的缺乏导致死亡受体的细胞表面表达增强，外源性凋亡信号传导的激活和细胞因子分泌减少。令人惊讶的是，蛋白质线粒体抗病毒信号传导（MAVS），这是RLR信号传导的必要衔接子和LGP 2的已知结合伴侣，是促进T细胞存活所不需要的。这些发现表明LGP 2以MAVS非依赖性方式发挥功能以促进T细胞免疫。我们的研究已经确定了在病毒感染过程中，RLR在先天性（DC）和适应性（T细胞）免疫之间的界面上的关键作用。然而，RLR调节T细胞免疫的机制还不清楚。在这个提议中，我们将评估两个特定的假设：（1）在WNV感染期间，DCs内的RLRs的功能调节活化、功能和T细胞引发;以及（2）在WNV感染期间，CD 4+和CD 8 + T细胞内的LGP 2功能调节保护性效应和记忆免疫应答。这些拟议的研究可能会揭示RLR的更广泛作用，并揭示宿主RNA解旋酶在病毒感染期间调节免疫力的新途径。这一提议可能会揭示新的治疗靶点和疫苗保护黄病毒感染的策略。