MR1 BIOCHEMICAL FEATURES AND IMMUNOLOGICAL FUNCTIONS

描述（由申请人提供）：消除病原体感染的细胞需要先天和获得性免疫系统中的细胞对其进行顺序识别。一种被统称为“先天T细胞”的独特类型的T细胞可以动态地桥接先天和获得性免疫反应。有趣的是，先天T细胞的激活可以受到mhc样分子或Ib类分子表达的限制。先天T细胞快速反应的能力源于它们缺乏对克隆扩增的依赖，这是由较少的鉴别受体-配体相互作用造成的。相比之下，传统的MHC分子在获得性免疫反应中限制了传统的CD4和CD8 T细胞，由于高度特异性的受体-配体相互作用，它们需要10-14天才能克隆扩增到足够的数量。本次资助的实验将表征新型Ib类分子MR1，该分子在哺乳动物中具有进化保守性，并以依赖于共生菌群和B细胞的方式限制粘膜相关不变T细胞或MAIT细胞的发育。MAIT细胞具有与先天T细胞功能一致的几个特征，包括i)不变的T细胞受体α链，ii)快速释放细胞因子的能力，以及iii)明显识别进化上保守的配体。然而，MR1配体的性质和MAIT细胞的生理作用都是未知的。在这个应用程序中，我们将测试MAIT细胞是否检测结核分枝杆菌感染的细胞，并且是宿主抵抗这种病原体的关键组成部分。此外，我们将阐明MR1配体的性质，其呈现的途径，以及配体/MR1复合物的晶体结构。MR1抗原呈递到MAIT细胞的细胞、分子和结构解剖将关键地确定该途径在细菌保护性免疫中的机制和重要性。

DESCRIPTION (provided by applicant): Elimination of pathogen-infected cells requires their sequential recognition by cells in the innate and acquired immune systems. A unique category of T cells collectively referred to as 'innate T cells' kinetically bridge the innate and acquired immune responses. Interestingly, the activation of innate T cells can be restricted by the expression of MHC-like molecules or class Ib molecules. The ability of innate T cells to respond rapidly stems from their lack of dependence on clonal expansion, resulting from less discriminating receptor-ligand interactions. By comparison, classical MHC molecules restrict conventional CD4 and CD8 T cells in the acquired immune response, and they require 10-14 days to clonally expand to sufficient numbers due to highly specific receptor-ligand interactions. The experiments in this grant will characterize the novel class Ib molecule MR1 that is evolutionarily conserved in mammals and restricts the development of mucosal-associated invariant T cells or MAIT cells in a manner dependent upon the commensal flora and B cells. MAIT cells have several features consistent with their function as innate T cells including i) invariant T cell receptor alpha chains, ii) the ability to rapidly release cytokines, and iii) apparent recognition of an evolutionarily conserved ligand. However, the nature of the MR1 ligand is unknown as is the physiological role of MAIT cells. In this application we will test whether MAIT cells detect Mycobacterium tuberculosis-infected cells and are critical components of host resistance to this pathogen. In addition, we will elucidate the nature of the MR1 ligand, the pathway by which it is presented, and the crystal structure of a ligand/MR1 complex. Cellular, molecular and structural dissection of MR1 antigen presentation to MAIT cells will critically define the mechanism and importance of this pathway in protective immunity to bacteria.