The Functional Role and Genetic Control of Invariant HLA-E T Cells in IBD Risk an

虽然许多工作已经探索了免疫调节在IBD中的作用，但在人类中这种作用的遗传学是有限的，调节性T细胞的抗原特异性知之甚少，并且缺乏对其治疗操作的策略。在上一个奖项期间，项目3的研究发现了一种新的免疫调节T细胞群，称为不变的HLA-E T细胞（小鼠中的Qa-1），对经历分子应激反应的靶细胞的普遍抗原复合物（HLA-E/Hsp60.4肽）具有抗原特异性。这种不变的T细胞群体依赖于肠道微生物组成，并且细胞溶解靶向活化的免疫细胞类型，从而在动物IBD模型中产生体内保护。新的合作工作表明，HLA-E等位基因影响UC疾病的严重程度，某些抑制性NK受体/HLA结合伴侣（K1 R2 DL 2/3和HLA-C1）都可以改变CD风险，并影响不变的HLA-E T细胞水平。 该项目测试了两个假设：（a）具有控制抑制性NK受体/HLA对的基因座或微生物血清学基因变异的患者将具有减少的粘膜不变T细胞;和（B）具有这些基因变异组合的患者将具有更严重的炎症和更严重的临床病程。这些假设将通过确定（1）恒定HLA-E T细胞的组织分布和功能;（2）抑制性NK受体/MHCI和Qa-1的遗传效应来检验。（鼠HLA-E同源物）对小鼠中恒定Qa-1 T细胞免疫调节的效率和机制的影响;和（3）HLA-C1、K1 R2 DL 2/3、HLA-E、NKG 2A和抗微生物抗体（水平和相关遗传基因座）对不变HLA-E T细胞和疾病严重程度的遗传相互作用。 如果成功，这些研究将揭示两类受体的遗传基因座和肠道微生物相互作用中的宿主性状如何调节一类新的调节性T细胞及其在CD和UC疾病严重程度中的作用。这种遗传特征可将患者分为这种免疫调节缺陷模式及其潜在的治疗干预。

While much work has explored the role of Immunoregulation in IBD, the genetics for this role In human is limited, their antigenic specificities of regulatory T cells are poorly understood, and strategies for their therapeutic manipulation are lacking. During the previous award period, studies in Project 3 uncovered a new immunoregulatory T cell population, termed invariant HLA-E T cells (Qa-1 in mice), with antigenic specificity for a prevalent antigenic complex (HLA-E/Hsp60.4 peptide) characteristic of target cells undergoing the molecular stress response. This Invariant T cell population Is dependent on commensal microbial composition, and cytolytically targets activated immune cell types yielding In vivo protection In animal IBD models. New collaborative work suggests that HLA-E alleles affect UC disease severity, and that certain inhibitory NK receptors/HLA binding partners (K1R2DL2/3 and HLA-C1) both modify CD risk, and affect invariant HLA-E T cell levels. This project tests two hypotheses: (a) patients with gene variants for loci controlling inhibitory NK receptor/HLA pairs, or for microbial serologies, will have reduced mucosal invariant T cells; and (b) patients with combinations of those gene variants will have more severe inflammation, and more severe clinical course. These hypotheses will be tested by determining (1) the tissue distribution and function of invariant HLA-E T cells; (2) the genetic effect of inhibitory NK receptor/MHCI and Qa-1 (the murine HLA-E homologue) on the efficiency and mechanism of Invariant Qa-1 T cell immunoregulation in mice; and (3) the genetic interaction of HLA-C1, K1R2DL2/3, HLA-E, NKG2A, and anti-microbial antibodies (levels and associated genetic loci) on Invariant HLA-E T cells and disease severity. If successful, these studies will reveal how genetic loci for two classes of receptors, and host traits in commensal microbial interaction, modulate a new class of regulatory T cells and their role In severity of disease in CD and UC. Such genetic traits to stratify patients for this mode of immunoregulation deficiency and its potential therapeutic Intervention.