Antigen Recognition by Gamma Delta T Cells

描述（由申请人提供）：T细胞根据其α或γ T细胞抗原受体的表达分为两个亚群。由于γ - δ T细胞分泌Thl细胞因子，杀死被感染的细胞，并在人体的许多不同感染中扩增（占外周血中所有T细胞的50%），它们可能在人体对感染的免疫中发挥重要作用。γ - T细胞在小鼠免疫中的重要性已经确立，因为缺乏γ - T细胞的小鼠会死于几种细菌的感染。γ - T细胞在自身免疫中也很重要，因为它们调节小鼠自身免疫aa - T细胞反应。我们发现，人类γ δ T细胞的主要亚群独特地识别非肽戊烯基焦磷酸盐、烷基胺和双磷酸盐以及特定的淋巴瘤。焦磷酸异戊烯基，如焦磷酸异戊烯基，是在细菌和人体内发现的类异戊二烯化合物必不可少的生物合成前体。我们现在已经确定了γ δ T细胞的主要细菌抗原为(E)-4-羟基-3-甲基-但-2-烯基焦磷酸（HMBPP）。HMBPP是细菌和原虫特异性途径合成焦磷酸异戊烯基（IPP）的中间体，也是γ - δ T细胞的有效刺激物。双膦酸盐是一种结构类似于HMBPP的药物，也能刺激Vgamma2Vdelta2 T细胞。我们现在发现了一种新的非肽抗原递呈分子存在的证据。我们假设Vgamma2Vdelta2 T细胞可以识别来自外部病原体、双磷酸盐和内源性IPP的HMBPP，这些IPP是由一种新的抗原呈递分子呈递的。Vgamma2Vdelta2 TCR识别非肽抗原和呈递分子的复合体，导致？d T细胞活化和效应功能。在这样做的过程中，γ δ T细胞使用它们的tcr作为模式识别受体，通过桥接先天免疫系统和适应性免疫系统，促进人类对感染和肿瘤的免疫，以及对自身免疫性疾病的控制。在此，我们建议进一步确定γ - δ T细胞识别非肽抗原的分子基础。在Aim I中，我们将鉴定Vgamma2Vdelta2 TCR中非肽、肿瘤和超抗原识别所必需的关键氨基酸。在目标2中，我们将表征非肽抗原的抗原呈递分子。在Aim 3中，我们将研究产生和调节细菌HMBPP的途径，并确定该途径在刺激γ δ T细胞中的重要性。在Aim 4中，我们将确定双膦酸盐识别的机制和生物学功能。这些研究将为人类γ δ T细胞对非肽抗原的识别提供见解，并有助于阐明它们在免疫和自身免疫中的作用。

DESCRIPTION (provided by applicant): T cells are divided into two subsets based on their expression of alphabeta or gammadelta T cell antigen receptors. Since gammadelta T cells secrete Thl cytokines, kill infected cells, and expand during a number of different infections in man (up to 50% of all T cells in the peripheral blood), they are likely to play an important role in human immunity to infection. The importance of gammadelta T cells in murine immunity has been established since mice lacking Gammadelta T cells succumb to infections with several bacterial species. Gammadelta T cells are also important in autoimmunity since they regulate murine autoimmune aa T cell responses. We have found that the major subset of human gammadelta T cells uniquely recognize nonpeptide prenyl pyrophosphates, alkylamines, and bisphosphonates as well as specific lymphomas. Prenyl pyrophosphates, such as isopentenyl pyrophosphate, are essential biosynthetic precursors for isoprenoid compounds that are found in both bacteria and man. We have now identified the major bacterial antigen for gammadelta T cells as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). HMBPP is an intermediate in a bacterial- and protozoal-specific pathway for isopentenyl pyrophosphate (IPP) synthesis and a potent stimulator of gammadelta T cells. Bisphosphonates, which are drugs that are structurally similar to HMBPP, also stimulate Vgamma2Vdelta2 T cells. We now find evidence for the existence of a novel antigen presenting molecule for nonpeptide antigens. We hypothesize that Vgamma2Vdelta2 T cells recognize HMBPP from external pathogens, bisphosphonates, and endogenous IPP that are presented by a novel antigen presenting molecule. The Vgamma2Vdelta2 TCR recognizes a complex of the nonpeptide antigen and the presenting molecule resulting in ?d T cell activation and effector function. In so doing, gammadelta T cells use their TCRs as pattern recognition receptors and contribute to human immunity to infections and tumors and to the control of autoimmune diseases by bridging the innate and adaptive immune systems. Here we propose to further define the molecular basis for the recognition of nonpeptide antigens by gammadelta T cells. In Aim I, we will identify critical amino acids in the Vgamma2Vdelta2 TCR that are required for nonpeptide, tumor, and superantigen recognition. In Aim 2, we will characterize the antigen presenting molecule for nonpeptide antigens. In Aim 3, we will study the pathways that produce and regulate bacterial HMBPP and determine the importance of this pathway in stimulating gammadelta T cells. In Aim 4, we will determine the mechanism and biological function of bisphosphonate recognition. These studies will provide insights into nonpeptide antigen recognition by human gammadelta T cells and should help clarify their role in immunity and autoimmunity.