Immune Tolerance Mediated by Negative Costimulatory Molecules

描述(申请人提供)：维持对自身组织的免疫耐受性的分子机制尚不清楚。T细胞的激活和耐受是由先天免疫系统调节的，重要的是通过共刺激分子。T细胞在无阳性协同作用(CD28和ICOS)的情况下被激活，导致其耐受和无能，这是静息状态下T细胞外周耐受的主要机制。另一方面，其他共刺激途径，如CTLA4和PD-1，已被发现抑制T细胞的激活。因此，B7共刺激分子家族的成员，通过它们在CD28家族中的受体，在决定T细胞的激活或自我耐受方面发挥着重要的作用。我们最近在小鼠体内发现并鉴定了两个新的类B7抑制分子--B7-H3和B7S1。阻断它们的抗体在体内加剧了实验性变态反应性脑脊髓炎(EAE)疾病。BTNL2是我们最近鉴定的一种丁咯菲林分子，它能与活化的T细胞结合并抑制其增殖。尽管近年来发现了大量的T细胞抑制物，但其在免疫耐受调节中的具体生理功能尚不清楚。在这个应用中，我们建议比较B7-H3、B7S1和BTNL2在免疫耐受中的作用，特别是通过分析它们在外周耐受和自身免疫性疾病模型发病机制中的作用。首先，我们研究了B7-H3和B7S1在外周耐受机制中的作用。其次，我们将研究B7-H3和B7S1在自身免疫性疾病模型中的作用。最后，我们将研究BTNL2的表达和功能。这些研究将极大地提高我们对这些新的共刺激分子在免疫耐受调节中的理解。

DESCRIPTION (provided by applicant): The molecular mechanisms whereby the immune tolerance to self tissues is maintained are not well understood. T cell activation and tolerance is regulated by the innate immune system, importantly through co-stimulatory molecules. Activation of T cells in the absence of positive cositmulation (CD28 and ICOS) results in their tolerance and anergy, which is the main mechanism for peripheral tolerance of T cells in resting states. On the other hand, other costimulatory pathways, such as CTLA4 and PD-1 have been discovered to inhibit T cell activation. Thus, members of the B7 costimulator family, through their receptors in the CD28 family, play essential roles in determining T cell activation or self-tolerance. We have recently identified and characterized two new B7-like inhibitory molecules in mouse- B7-H3 and B7S1. Blocking antibodies against them exacerbated experimental allergic encephalomyelitis (EAE) disease in vivo. BTNL2 is a butyrophilin molecule we recently characterized that binds to activated T cell and inhibits their proliferation. Despite a large number of T cell inhibitors identified in the recent years, their specific physiological function in regulation of immune tolerance has not been well understood. In this application, we propose to compare the actions by B7-H3, B7S1 and BTNL2 in immune tolerance, specifically by analyzing their roles in peripheral tolerance and in pathogenesis of autoimmune disease models. First, we characterize the function of B7-H3 and B7S1 in peripheral tolerance mechanisms. Secondly, we will study the roles of B7- H3 and B7S1 in autoimmune disease models. Lastly, we will examine the expression and function of BTNL2. These studies will greatly improve our understanding of these novel costimulatory molecules in immune tolerance regulation.