MR1 BIOCHEMICAL FEATURES AND IMMUNOLOGICAL FUNCTIONS

MR1 生化特征和免疫功能

• 批准号: 8459413
• 负责人: Daved H. Fremont
• 金额: $ 35.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459413
• 关键词: Antigen Presentation; B-Lymphocytes; Bacteria; Biochemical; CD8B1 gene; Categories; Cells; Clonal Expansion; Complex; Dependence; Development; Dissection; Grant; Host resistance; Immune response; Immune system; Immunity; Infection; Ligands; Mammals; Molecular; Mucosal Immune Responses; Mucous Membrane; Mycobacterium tuberculosis; Nature; Pathway interactions; Physiological; Role; Structure; T-Cell Receptors alpha-Chain; T-Lymphocyte; T-Lymphocyte Subsets; Testing; cytokine; disorder control; novel; pathogen; public health relevance; receptor; research study; stem

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.

描述（由申请人提供）：消除病原体感染的细胞需要它们被先天性和获得性免疫系统中的细胞顺序识别。统称为“先天性T细胞”的独特类别的T细胞在动力学上桥接先天性和获得性免疫应答。有趣的是，先天性T细胞的激活可以受到MHC样分子或Ib类分子表达的限制。先天性T细胞快速反应的能力源于它们缺乏对克隆扩增的依赖性，这是由较少的识别性受体-配体相互作用引起的。相比之下，经典的MHC分子在获得性免疫应答中限制常规的CD 4和CD 8 T细胞，并且由于高度特异性的受体-配体相互作用，它们需要10-14天来克隆扩增到足够的数量。在这项授权的实验将表征新的Ib类分子MR 1是进化上保守的哺乳动物和限制发展的粘膜相关的不变的T细胞或MAIT细胞的方式依赖于肠道植物群和B细胞。MAIT细胞具有与其作为先天性T细胞的功能一致的若干特征，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，和iii）进化上保守的配体的表观识别。然而，MR 1配体的性质是未知的，因为是MAIT细胞的生理作用。在本申请中，我们将测试MAIT细胞是否检测结核分枝杆菌感染的细胞，以及是否是宿主对该病原体的抗性的关键组成部分。此外，我们将阐明MR 1配体的性质，它是通过何种途径提出的，以及配体/MR 1复合物的晶体结构。MR 1抗原呈递给MAIT细胞的细胞、分子和结构解剖将严格定义该途径在细菌保护性免疫中的机制和重要性。