Immune Tolerance Mediated by Negative Costimulatory Molecules

描述（由申请人提供）：维持自身组织免疫耐受的分子机制尚不清楚。T细胞的激活和耐受性是由先天免疫系统调节的，主要是通过共刺激分子。T细胞在缺乏正稳态（CD28和ICOS）的情况下被激活，导致它们的耐受性和能量，这是T细胞在静息状态下外周耐受性的主要机制。另一方面，其他共刺激通路，如CTLA4和PD-1已被发现抑制T细胞活化。因此，B7共刺激因子家族的成员通过其在CD28家族中的受体，在决定T细胞活化或自我耐受中发挥重要作用。我们最近在小鼠中发现并表征了两个新的b7样抑制分子- B7-H3和B7S1。体内抗它们的阻断抗体加重实验性变应性脑脊髓炎（EAE）。BTNL2是我们最近发现的一种与活化的T细胞结合并抑制其增殖的亲丁酸蛋白分子。尽管近年来发现了大量的T细胞抑制剂，但它们在调节免疫耐受中的特定生理功能尚未得到很好的理解。在本应用中，我们拟比较B7-H3、B7S1和BTNL2在免疫耐受中的作用，具体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，我们描述了B7-H3和B7S1在外周耐受机制中的功能。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。这些研究将大大提高我们对这些新型共刺激分子在免疫耐受调节中的认识。

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.