Role of TIM family of Genes in Regulating Autopathogenic T Cell Responses

TIM 基因家族在调节自病性 T 细胞反应中的作用

• 批准号: 8378181
• 负责人: VIJAY K. KUCHROO
• 金额: $ 40.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378181
• 关键词: Address; Affect; Animal Model; Antibodies; Antigen-Presenting Cells; Asthma; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Binding; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aggregation; Cell Death; Cells; Chimeric Proteins; Complex; Data; Dendritic Cells; Disease model; Effector Cell; Experimental Autoimmune Encephalomyelitis; Galactose Binding Lectin; Gene Family; Generations; Immune; Immune response; Immune system; Immunity; Immunoglobulins; In Vitro; Informal Social Control; Interferons; Investigation; Knockout Mice; Ligands; Mediating; Microglia; Modeling; Mucins; Multiple Sclerosis; Mus; Myelin Basic Proteins; Neuraxis; Pathogenesis; Play; Production; Reagent; Regulation; Relative (related person); Role; Running; Signal Transduction; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Th2 Cells; Time; Transgenic Organisms; Tumor Immunity; Viral; cell type; in vivo; peripheral tolerance; release of sequestered calcium ion into cytoplasm; response; selective expression; tool

The recently discovered Tim (T cell Immunoglobulin and Mucin domain) gene family has emerged as an important player in immune regulation. We identified Tim-3 as a molecule expressed specifically on CD4+ Th1 but not Th2 cells. The interaction of Tim-3 with its ligand, galectin-9, triggers cell death in Th1 cells, thereby dampening Th1 immunity. Tim-3 is also expressed on CDS* Tc1 but not Tc2 cells. However, whether Tim-3 similarly regulates Tc1 effector cells has not been examined. Interestingly, we have now found that Tim-3 is expressed on all dendritic cells (DCs), the major antigen presenting cells (APCs) of the immune system and on central nervous system (CNS) microglia, the local APCs in the CNS. These observations raise the possibility that Tim-3 may regulate the adaptive immune response via its expression on APCs. Indeed, we have found that Tim-3, contrary to its role in dampening Th1 immunity via its expression on Th1 cells, may promote Th1 immunity via its expression on APCs. This suggests that Tim-3 may serve opposing roles in the innate and adaptive immune systems. Tim-1 is expressed on all activated CD4+ T cells with Th2 cells expressing slightly higher levels relative to Th1 cells. Tim-1 can function as a costimulatory molecule and appears to be important in the induction of T cell tolerance. These observations support an important role for Tim-1-mediated regulation of CD4+ T cell responses. However, the effects of Tim-1 in Th1 cells, and the newly identified subset of Th-17 cells, have not been examined. In addition, we have found that Tim-1 is expressed on all CDS* T cells directly ex vivo, raising the possibility that Tim-1 may regulate CDS* T cell responses. We have developed several new antibodies, fusion proteins and transgenic and knock-out mice that will allow for the first time a detailed investigation of the role of Tim-3 in DCs, CNS microglia and CDS* Tc1 cells and Tim-1 in Th1, Th-17 and CDS* T cells. Using these tools, we propose to 1) Determine the function of Tim-3 in the innate immune system specifically on DCs and CNS derived microglial cells, 2) Define the role of Tim-3 in the generation and regulation of self-reactive CDS T cells, 3) Determine the role of Tim-1 signaling in the generation and effector function of encephalitogenic T cells including Th1, Th-17 and CDS* T cells. The studies proposed here will analyze the role of Tim-3 and Tim-1 in the regulation of autoimmune responses by affecting the function of DCs, CNS microglia, Th-1, Th-17, and CDS* T cells, the subsets of immune cells in which the functional role of Tim-1 and Tim-3 is not known.

最近发现的Tim（T细胞免疫球蛋白和粘蛋白结构域）基因家族已出现为 免疫调节的重要参与者。我们将tim-3确定为特异性表达的分子 CD4+ TH1但没有Th2细胞。 Tim-3与其配体Galectin-9的相互作用触发TH1的细胞死亡 细胞，从而抑制Th1免疫力。 TIM-3也在CDS* TC1上表示，但不表示TC2细胞。 但是，尚未检查TIM-3是否类似地调节TC1效应细胞。 有趣的是，我们现在发现TIM-3在所有树突状细胞（DC）（主要抗原）上表达 免疫系统和中枢神经系统（CNS）小胶质细胞的细胞（APC），局部 中枢神经系统中的APC。这些观察结果提出了TIM-3可能调节适应性免疫的可能性 通过其在APC上的表达响应。确实，我们发现Tim-3与其在抑制中的作用相反 Th1免疫通过其在Th1细胞上的表达，可以通过其在APC上的表达来促进Th1免疫。 这表明TIM-3可能在先天和适应性免疫系统中起作用。 TIM-1在所有活化的CD4+ T细胞上表达，Th2细胞相对表达略高的水平 到Th1细胞。 TIM-1可以用作共刺激分子，并且在诱导中似乎很重要 T细胞耐受性。这些观察结果支持TIM-1介导的CD4+调节的重要作用 T细胞反应。但是，TIM-1在Th1细胞中的影响以及新鉴定的TH-17子集 细胞，尚未检查。另外，我们发现TIM-1在所有CDS* T细胞上都表示 直接离体，提高了TIM-1可以调节CDS* T细胞反应的可能性。 我们已经开发了几种新抗体，融合蛋白以及转基因和敲除小鼠 首次允许对TIM-3在DC，CNS小胶质细胞和CDS* TC1中的作用进行详细研究 细胞和TIM-1中的Th1，Th-17和CdS* T细胞中的细胞和TIM。使用这些工具，我们建议1）确定 TIM-3在天生免疫系统中的功能专门在DC和CNS衍生小胶质细胞上的功能，2） 定义TIM-3在自反应性CD T细胞的产生和调节中的作用，3）确定 TIM-1信号传导在脑源性T细胞的产生和效应子功能中的作用，包括Th1， TH-17和CDS* T细胞。 这里提出的研究将分析TIM-3和TIM-1在自身免疫调节中的作用 通过影响DC，CNS小胶质细胞，TH-1，TH-17和CDS* T细胞的功能来响应 TIM-1和TIM-3的功能作用的免疫细胞尚不清楚。