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

虽然许多工作探索了免疫调节在IBD中的作用，但对人类这种作用的遗传学研究有限，对调节性T细胞的抗原特异性了解很少，缺乏治疗操作的策略。在之前的获奖期间，项目3的研究发现了一种新的免疫调节T细胞群，称为不变的人类白细胞抗原-E T细胞(小鼠中的Qa-1)，具有对经历分子应激反应的目标细胞的普遍抗原复合体(HLA-E/Hsp60.4肽)的抗原特异性。这种不变的T细胞群依赖于共生微生物组成，并在动物IBD模型中以激活的免疫细胞类型为细胞溶解靶点，产生体内保护作用。新的合作研究表明，人类白细胞抗原-E等位基因影响UC疾病的严重程度，某些抑制性NK受体/人类白细胞抗原结合伙伴(K1R2DL2/3和人类白细胞抗原-C 1)都可以改变慢性萎缩性胃炎的风险，并影响不变的人类白细胞抗原-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/人类白细胞抗原对的基因变异的患者，或具有微生物血清的患者，粘膜不变T细胞将减少；以及(B)具有这些基因变异组合的患者将有更严重的炎症和更严重的临床病程。这些假说将通过确定(1)不变的HLA-E T细胞的组织分布和功能；(2)抑制性NK受体/MHCI和Qa-1(小鼠的HLA-E同源物)对小鼠不变的Qa-1 T细胞免疫调节的效率和机制的遗传效应；以及(3)HLA-C1、K1R2DL2/3、HLA-E、NKG2A和抗微生物抗体(水平和相关的遗传位点)对不变的HLA-E T细胞和疾病严重程度的遗传相互作用来检验。 如果成功，这些研究将揭示两类受体的遗传位点和共生微生物相互作用中的宿主特征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。这种遗传特征将这种免疫调节缺陷模式的患者分层，并进行潜在的治疗干预。

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.