T cell responses to CD1-restricted lipids in tuberculosis

项目摘要 活化的巨噬细胞T细胞是宿主防御结核分枝杆菌（Mtb）感染的主要手段， 结核病（TB）。几十年来，T细胞被认为只识别与之结合的肽抗原 在MHC基因座中编码的多态性抗原呈递分子。然而，发现人类 CD 1蛋白将分枝杆菌抗原呈递给T细胞提供了关于 宿主防御中的T细胞。首先，R 01方案的基础研究表明， 结核分枝杆菌糖脂、磷脂和脂肽对大肠杆菌和大肠杆菌T细胞的作用。因此，脂质现在必须 被认为是人类免疫系统的多种天然抗原。其次，尽管MHC 基因座是人类基因组中最具多态性的基因，CD 1基因的非多态性性质创造了一个 T细胞反应不限于个体基因型的情况。这样的“供体-非限制性T 细胞具有简化的抗原识别模式和T细胞受体的使用， 疗法基于大量已发表和未发表的数据，这项以人为本的更新提案寻求 为了测试抗原识别的一般模型，其中T细胞受体（TCR）结合到屋顶结构上， CD 1，或远离屋顶接触细菌抗原。使用最近验证的人CD 1a、CD 1b和 CD 1c四聚体，我们将发现新的保守的TCR，相当于在CD 1d系统中的NKT TCR。 我们建议确定新发现的人类先天性T细胞类型的效应功能，重点是 基因定义了一个先天梯度和已知的效应功能，需要保护宿主免受 Mtb.最后，我们将联合收割机新生产的试剂，包括四聚体、转染子和单克隆 抗体，使用豚鼠作为一个易于处理的模型，用于研究宿主T细胞反应，在肺和 时间这些研究有助于一个创新的观点，即人类T细胞系统识别和响应 脂质抗原

Project Summary Activation of  T cells is the mainstay of host defense against Mycobacterium tuberculosis (Mtb) infection and tuberculosis disease (TB). For decades,  T cells were thought to recognize solely peptide antigens bound to polymorphic antigen presenting molecules encoded in the MHC locus. However, the discovery that human CD1 proteins present mycobacterial antigens to T cells provides fundamentally new perspectives on the role of T cells in host defense. First, the foundational studies for this R01 proposal showed that CD1 proteins present mycobacterial glycolipids, phospholipids and lipopeptides to  and  T cells. Thus, lipids must now be considered a diverse class of natural antigens for the human immune system. Second, whereas the MHC locus is the most polymorphic of the human genome, the non-polymorphic nature of CD1 genes creates a situation in which T cell responses are not restricted to an individual’s genotype. Such ‘donor-unrestricted T cells’ have simplified patterns of antigen recognition and T cell receptor usage that could be exploited for therapy. Building on substantial published and unpublished data, this human-focused renewal proposal seeks to test a general model of antigen recognition in which T cell receptors (TCRs) bind onto a roof structure in CD1, or shift away from the roof to contact bacterial antigen. Using recently validated human CD1a, CD1b and CD1c tetramers, we will discover new conserved TCRs that are equivalent to NKT TCRs in the CD1d system. We propose to determine the effector functions of newly discovered innate T cell types in humans, focusing on genes that define an innateness gradient and the known effector functions needed to protect the host against Mtb. Finally, we combine newly produced reagents, including tetramers, transfectants and monoclonal antibodies, to use the guinea pig as a tractable model for study of host T cell responses in the lung and over time. These studies contribute to an innovative view that the human T cell system recognizes and responds to lipid antigens.