TCR signal strength in thymic selection

胸腺产生大量的MHC限制性、自我耐受的CD4辅助细胞和CD8细胞溶解T细胞参与适应性免疫反应。这种“传统T细胞”是在低亲和力TCR与MHC分子相互作用的反应中产生的，MHC分子在胸腺皮质区显示出多样性的自肽。相比之下，高亲和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物的存活和分化。这些效应物包括foxP3+自然调节性T细胞（Treg）、上皮内淋巴细胞（IEL）和CD1d限制性自然杀伤T细胞（NKT）。本研究将探讨高亲和力TCR信号在克隆缺失和NKT效应分化中的作用。在之前的一段时间里，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在早期（DP）阶段删除的克隆与在晚期（SP）阶段删除的克隆的库，反应性和结构。具体来说，我们假设早期缺失的克隆与MHC有明显的相互作用，而晚期缺失的克隆具有典型的肽-MHC反应性。提出的实验将表征由早期和晚期删除克隆的逃逸所产生的不同的自身免疫病理。脂质特异性自然杀伤T细胞（NKT）来源于胸腺祖细胞，它们在胸腺的强信号中存活下来，并发展成3个主要的效应亚群，产生不同的细胞因子，如我们在上一篇文章中所示。其中一个亚群（NKT2）在稳定状态下产生IL-4，影响免疫细胞发育的多个方面，促进II型免疫反应。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NKT2产生的IL-4对淋巴细胞、髓细胞和基质细胞的影响；并定义NKT细胞如何进入独特的组织环境来影响免疫反应。

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.