TCR signal strength in thymic selection

胸腺产生丰富的MHC限制性、自身耐受性CD 4辅助和CD 8细胞溶解性T细胞以参与适应性免疫应答。这种“常规T细胞”在低亲和力TCR与MHC分子的相互作用下发育，所述MHC分子在胸腺的皮质区域中显示多样性的自身肽。相反，高亲和力相互作用导致克隆缺失，但在某些情况下也可以支持成熟调控效应子的存活和分化。这些效应子包括foxP 3+天然调节性T细胞（Treg）、上皮内淋巴细胞（IEL）和CD 1d限制性自然杀伤T细胞（NKT）。该建议将探索高亲和力TCR信号传导在克隆缺失和NKT效应分化中的作用。在前一时期，我们开发了一种新的方法来捕获通常注定要删除的T细胞克隆。在这里，我们应用这种方法来研究的剧目，反应性和结构的克隆删除在早期（DP）阶段与那些删除在晚期（SP）阶段。具体来说，我们假设，早期删除克隆有一个独特的相互作用与MHC是依赖于肽，而后期删除克隆有经典的肽-MHC反应性。实验提出，将表征不同的自身免疫性病理所创建的早期与晚期删除克隆逃逸。脂质特异性自然杀伤T细胞（NKT）来源于胸腺祖细胞，其在胸腺中的强信号传导中存活，并发育成3种主要的效应子亚群，其产生不同的细胞因子，如我们在前一时期所示。这些亚群之一（NKT 2）在稳态下产生IL-4，这影响免疫细胞发育的多个方面，以促进II型免疫应答。我们的研究将确定控制NKT细胞分化的关键分子;进一步表征NKT 2产生的IL-4对淋巴细胞，骨髓细胞和基质细胞的影响;并确定NKT细胞如何运输到独特的组织环境以影响免疫反应。

The thymus produces an abundance of MHC restricted, self-tolerant CD4 helper and CD8 cytolytic T cells to participate in adaptive immune responses. Such “conventional T cells” develop in response to low-affinity TCR interactions with MHC molecules that display a diversity of self-peptides in the cortical region of the thymus. In contrast, high affinity interactions result in clonal deletion, but can also support the survival and differentiation of mature regulatory effectors in some contexts. These effectors include foxP3+ natural regulatory T cells (Treg), intraepithelial lymphocytes (IEL), and CD1d restricted natural killer T cells (NKT). This proposal will explore the role of high-affinity TCR signaling in clonal deletion and NKT effector differentiation. In the previous period we developed a novel approach to capturing T cell clones that are normally destined for deletion. Here we apply this approach to study the repertoire, reactivity, and structure of clones deleted at the early (DP) stage versus those deleted at the late (SP) stage. Specifically we hypothesize that early deleted clones have a distinct interaction with MHC that is less dependent on peptide, whereas late deleted clones have classic peptide-MHC reactivity. Experiments are proposed that will characterize the distinct autoimmune pathologies created by the escape of early versus late deleted clones. Lipid-specific natural killer T cells (NKT) are derived from thymic progenitors that survive strong signaling in the thymus and develop into 3 major effector subsets that produce distinct cytokines, as we showed in the previous period. One of these subsets (NKT2) produces IL-4 in the steady state and this influences multiple aspects of immune cell development to promote type II immune responses. Our research will identify key molecules controlling the differentiation of NKT cells; further characterize the effects of NKT2 produced IL-4 on lymphoid, myeloid, and stromal cells; and define how NKT cells traffic to unique tissue environments to impact immune responses.