Antigen Recognition by Gamma Delta T Cells

描述(申请人提供)：T细胞根据其表达的Alphabeta或Gammadelta T细胞抗原受体分为两个亚群。由于Gammadelta T细胞分泌Th1细胞因子，杀死感染的细胞，并在人类许多不同的感染过程中(高达外周血中所有T细胞的50%)扩张，它们很可能在人类对感染的免疫中发挥重要作用。自从缺乏Gammadelta T细胞的小鼠被多种细菌感染以来，Gammadelta T细胞在小鼠免疫中的重要性已经得到证实。Gammadelta 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性AA T细胞的反应。我们已经发现，人类Gammadelta T细胞的主要亚群唯一地识别非肽戊基焦磷酸、烷基胺和双膦酸盐以及特定的淋巴瘤。异戊烯基焦磷酸盐是异戊二烯类化合物的重要生物合成前体，广泛存在于细菌和人体中。我们现在已经确定Gammadelta T细胞的主要细菌抗原是(E)-4-羟基-3-甲基-2-烯基焦磷酸(HMBPP)。HMBPP是细菌和原生动物特异性合成异戊烯焦磷酸(IPP)途径的中间体，也是Gammadelta T细胞的有效刺激因子。双膦酸类药物在结构上类似于HMBPP，它也能刺激VGamma2Vdelta2T细胞。我们现在发现了一种新的非肽类抗原提呈分子存在的证据。我们假设VGamma2Vdelta2T细胞识别HMBPP来自外部病原体、双膦酸盐和内源性IPP，它们是由一种新的抗原提呈分子呈递的。VGamma2Vdelta2TCR识别非肽抗原和呈递分子的复合体，导致D T细胞激活和效应器功能。在此过程中，Gammadelta T细胞将其TCR用作模式识别受体，通过连接先天免疫系统和获得性免疫系统，促进人类对感染和肿瘤的免疫，并有助于控制自身免疫性疾病。在此，我们建议进一步确定Gammadelta T细胞识别非肽抗原的分子基础。在目标I中，我们将确定VGamma2Vdelta2TCR中的关键氨基酸，这些氨基酸是非肽、肿瘤和超抗原识别所必需的。在目标2中，我们将表征非肽抗原的抗原提呈分子。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Gammadelta T细胞中的重要性。在目标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Gammadelta T细胞识别非肽抗原提供见解，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.