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免疫系统和后天免疫系统中的细胞顺序识别。一类独特的T细胞统称为“先天T细胞”，在动态上连接先天免疫反应和后天免疫反应。有趣的是，天然T细胞的激活可以受到MHC类分子或Ib类分子表达的限制。与生俱来的T细胞快速反应的能力源于它们不依赖于克隆扩增，这是由于较少区分受体-配体相互作用的结果。相比之下，经典的MHC分子在获得性免疫反应中限制了传统的CD4和CD8T细胞，由于高度特异的受体-配体相互作用，它们需要10-14天才能克隆扩增到足够数量。这项资助中的实验将表征在哺乳动物中进化保守的新型Ib类分子MR1，它以一种依赖于共生菌群和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细胞具有与其作为天然T细胞的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配体的性质尚不清楚，MAIT细胞的生理作用也是如此。在这项应用中，我们将测试MAIT细胞是否检测到结核分枝杆菌感染的细胞，以及是否是宿主抵抗这种病原体的关键成分。此外，我们还将阐明MR1配体的性质，提出它的途径，以及配体/MR1复合体的晶体结构。对MR1抗原呈递给MAIT细胞的细胞、分子和结构的剖析将关键地确定这一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.