Role of Costimulation in Control of the Effector and Regulatory T Cell Balance

T细胞共刺激通路在调节T细胞活化和耐受中起关键作用。最近的遗传学研究表明，共刺激分子控制许多人类自身免疫性疾病的遗传易感性。项目4将剖析CTLA-4和最近确定的共刺激途径的功能作用，包括共刺激受体CD 226，共抑制受体TIGIT及其配体PVR，在调节效应与调节T细胞反应之间的平衡，以及自身免疫的发展。这一关注是由托德博士、Wicker博士（项目1）和Hafler博士（项目2）的人类遗传学研究驱动的，这些研究已经确定了与发生自身免疫性疾病风险相关的CTLA-4和CD 226中的候选致病变体，以及我们对CTLA-4免疫调节功能的研究，以及我们对CD 226表达的CD 28依赖性上调和稳定的发现。我们将验证我们的假设，即T细胞共刺激通路在调节致病性和非致病性之间的平衡中起着关键作用。 和保护性T细胞反应。为了验证这一假设，我们提出了以下具体目标：1。研究CTLA-4如何控制效应T细胞和调节T细胞之间的平衡。我们将使用 CTLA-4条件性敲除小鼠（KO）分析CTLA-4如何控制效应和调节T细胞 发展和功能。2.研究CD 28/CTLA-4与CD 226/TIGIT通路之间的相互作用。我们将研究CD 28和CTLA-4如何调节CD 226亚型以及CD 226蛋白的表达，因为我们的初步数据表明，CD 28可能差异调节CD 226亚型的表达。我们还将检验CD 226表达失调可能导致CTLA-4K 0小鼠表型的假设，因为CD 28的消除消除了CD 226表型。在补充研究中，我们将研究⑶ 28对TIGIT +/-小鼠的活化表型的贡献。3.为了研究PVR的功能，重点是使用TIGIT-Fc和PVR KO小鼠的TIGIT/PVR相互作用抑制T细胞应答的机制。我们的目标是了解CD 28/CTLA-4和CD 226/TIGIT/PVR相互作用如何调节T细胞耐受和自身免疫。

T cell costimulatory pathways play key roles in regulating T cell activation and tolerance. Recent genetic studies suggest that costimulatory molecules control genetic susceptibility to many human autoimmune diseases. Project 4 will dissect the functional roles of CTLA-4 and the recently identified costimulatory pathway consisting of the costimulatory receptor CD226, the coinhibitory receptor TIGIT and their ligand PVR, in regulating the balance between effector versus regulatory T cell responses, and development of autoimmunity. This focus is driven by human genetic studies of Drs. Todd, Wicker (Project 1), and Dr. Hafler (Project 2) which have identified candidate causal variants in CTLA-4 and CD226 associated with risk of developing autoimmune diseases, together with our studies of the immunoregulatory functions of CTLA-4, and our finding of CD28-dependent upregulation and stabilization of CD226 expression. We will test our hypothesis that T cell costimulatory pathways play critical roles in regulating the balance between pathogenic and protective T cell responses. To test this hypothesis, we propose the following Specific Aims: 1. To investigate how CTLA-4 controls the balance between effector and regulatory T cells. We will use CTLA-4 conditional knockout mice (KO) to analyze how CTLA-4 controls effector and regulatory T cell development and function. 2. To investigate the interplay between the CD28/CTLA-4 with CD226/TIGIT pathways. We will investigate how CD28 and CTLA-4 regulate expression of CD226 isoforms as well as CD226 protein, since our preliminary data indicate that CD28 may differentially regulate CD226 isoform expression. We also will test the hypothesis that dysregulated CD226 expression may contribute to the phenotype of CTLA-4K0 mice, since elimination of CD28 abrogates the CD226 phenotype. In complementary studies, we will investigate the contribution of CD28 to the activated phenotype of TIGIT"'" mice. 3. To investigate the functions of PVR, focusing on mechanisms by which TIGIT/PVR interactions inhibit T cell responses using TIGIT-Fc and PVR KO mice. Our goals are to understand how the CD28/CTLA-4 and CD226/TIGIT/PVR interactions regulate T cell tolerance and autoimmunity.