Antigen Recognition by Gamma Delta T Cells

描述（由申请人提供）：根据α或γ δ T细胞抗原受体的表达，将T细胞分为两个亚群。由于γ δ T细胞分泌Thl细胞因子，杀死感染的细胞，并在人的许多不同感染期间扩增（高达外周血中所有T细胞的50%），因此它们可能在人对感染的免疫中起重要作用。γ δ T细胞在鼠免疫中的重要性已经被确立，因为缺乏γ δ T细胞的小鼠死于几种细菌的感染。γ δ T细胞在自身免疫中也很重要，因为它们调节鼠自身免疫性α α T细胞应答。我们已经发现，人类γ δ T细胞的主要子集独特地识别非肽异戊烯焦磷酸盐，烷基胺，双膦酸盐以及特定的淋巴瘤。异戊烯基焦磷酸（如异戊烯基焦磷酸）是类异戊二烯化合物的重要生物合成前体，类异戊二烯化合物存在于细菌和人类中。我们现已鉴定出γ δ T细胞的主要细菌抗原为（E）-4-羟基-3-甲基-丁-2-烯基焦磷酸（HMBPP）。HMBPP是异戊烯焦磷酸（IPP）合成的细菌和原生动物特异性途径中的中间体，也是γ δ T细胞的有效刺激剂。结构上与HMBPP相似的双膦酸盐药物也能刺激V γ 2 Vdelta 2 T细胞。我们现在发现了一种新的非肽类抗原呈递分子存在的证据。我们假设V γ 2 Vdelta 2 T细胞识别来自外部病原体、二膦酸盐和内源性IPP的HMBPP，这些HMBPP由新的抗原呈递分子呈递。V γ 2 V δ 2 TCR识别非肽抗原和呈递分子的复合物，导致？d T细胞活化和效应子功能。在这样做的过程中，γ δ T细胞使用其TCR作为模式识别受体，并通过桥接先天性和适应性免疫系统来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。在这里，我们建议进一步定义γ δ T细胞识别非肽抗原的分子基础。在目标I中，我们将确定V γ 2 V δ 2 TCR中的关键氨基酸，这些氨基酸是非肽、肿瘤和超抗原识别所需的。在目标2中，我们将描述非肽抗原的抗原呈递分子。在目标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。目的四是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新的见解，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.