TCR signal strength and iNKT cell subset development

项目摘要 不变的自然杀伤T（iNKT）细胞在多种生物学中的几种免疫应答中发挥核心作用。 从自身免疫、损伤和感染到妊娠和代谢疾病， 癌iNKT细胞的特征在于它们使用非常有限的T细胞抗原受体（TCR）库， 识别由CD 1d呈递的脂质抗原，CD 1d是一种非多态性的I类主要组织相容性复合物， 抗原呈递分子许多功能不同的iNKT细胞亚群，每个亚群都有倾向性 运输到不同的组织并在激活后分泌不同的细胞因子。虽然 显然，这些命运分配是在胸腺选择过程中赋予iNKT细胞的， 指导这些决定的环境线索是未知的。我们的初步数据显示，1）在野生型中， 在小鼠中，iNKT TCR的亲合力与iNKT细胞亚群和反映免疫应答的标志物的表达相关。 选择过程中的信号强度; 2）具有固定TCR库的小鼠中iNKT细胞的发育是 在不同的遗传背景下受到类似的影响; 3）V基因的使用和CDR 3基因序列对每个基因都是独特的 iNKT细胞亚群; 4）iNKT细胞发育的最早可定义阶段中的信号传导和基因表达， 在TCR与体内天然配体结合后，在TCR减少的小鼠中立即发生改变 发信号。这些小鼠在iNKT细胞亚群的发育中也表现出细胞内在缺陷。基于这些 在初步研究中，我们假设iNKT细胞的分化和功能是由TCR特异性决定的， 和信号强度。这一假设将通过追求以下具体目标来检验：1）确定 胸腺iNKT亚群组成的菌株差异的基础; 2）确定亲和力和配体的影响， TCR对iNKT细胞亚群发育的特异性。该提案具有创新性，因为它直接 探索了TCR对自身配体的特异性/亲和力在指定iNKT细胞亚群的发育中的作用。 这项拟议的研究意义重大，因为它将为我们了解iNKT细胞亚群的发育提供信息。 和动力学，免疫干预的先决条件，旨在操纵和优化iNKT细胞为基础的 治疗

Project Summary Invariant Natural Killer T (iNKT) cells play a central role in several immune responses in diverse biological contexts ranging from autoimmunity, injury and infections to pregnancy and metabolic disease as well as cancer. iNKT cells are characterized by their use of a very limited T cell antigen receptor (TCR) repertoire to recognize lipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like antigen-presenting molecule. A number of functionally distinct iNKT cell subpopulations, each with propensity to traffic to different tissues and to secrete different cytokines upon activation, have been defined. Although it is clear that these fate assignments are conferred upon iNKT cells during selection in the thymus, the environmental cues that direct these decisions are unknown. Our preliminary data show that 1) in wildtype mice, the avidity of the iNKT TCR correlates with iNKT cell subsets and the expression of markers reflecting strength of signaling during selection; 2) the development of iNKT cells in mice with a fixed TCR repertoire is affected similarly on different genetic backgrounds; 3) the V usage and CDR3 sequences are unique to each iNKT cell subset; 4) signaling and gene expression in the earliest definable stage of iNKT cell development, immediately after engagement of the TCR by natural ligands in vivo, is altered in mice with reduced TCR signaling. These mice also exhibit a cell intrinsic defect in development of iNKT cell subsets. Based on these preliminary studies, we hypothesize that iNKT cell differentiation and function is determined by TCR specificity and signal strength. This hypothesis will be tested by pursuing the following specific aims: 1) Determine the basis for strain differences in thymic iNKT subset composition; 2) Determine the effect of affinity and ligand- specificity of the TCR on development of iNKT cell subsets. The proposal is innovative because it directly explores the role of TCR specificity/affinity for self-ligands in specifying the development of iNKT cell subsets. The proposed research is significant because it will inform our understanding of iNKT cell subset development and dynamics, a pre-requisite to immune intervention aimed at manipulating and optimizing iNKT cell-based therapies.