Study of LY108 innate and adaptive immune responses

描述(由申请人提供)：本申请寻求资助旨在剖析自体配体细胞表面受体Ly108(Slamf6)如何控制实验性结肠炎发病机制中的适应性和先天免疫反应的研究。对基因明确的实验性IBD小鼠模型的研究导致了一种理解，即免疫系统和结肠的巨大抗原量之间微调平衡的扰动会导致疾病。我们开始剖析Treg细胞如何预防结肠炎，诱导致病的CD4+T细胞，如Th1，Th2或Th17，在固有层中扩张。然而，我们并不了解许多遗传和机制网络，这些网络参与了对结肠菌诱导的细菌抗原和/或小鼠抗原的先天和获得性免疫反应的调节。我们的一般假设是，由自身免疫基因Ly108编码的受体亚型，即Ly108-1、Ly108-2和Ly108-H1，控制着不同的结肠炎途径。正如我们的初步研究将证明的那样：i)Ly108的参与可以改善结肠炎；ii)Ly108调节不同的CD4+T细胞和NKT细胞的反应；以及iii)Ly108调节巨噬细胞或中性粒细胞对细菌的反应，很可能是因为Ly108作为“清道夫受体”进入吞噬小体。基本策略是剖析T细胞和吞噬细胞对共生菌的反应以及实验性结肠炎发病机制中Ly108的三种异构体失衡的后果。我们已经建立了系统，利用我们的大量新型转基因小鼠、我们的单抗和可溶性配体来证明受体异构体在疾病表现中相互作用的重要性。拟议的实验分为以下特定目标：特定目标#1：测试Ly108的三种异构体启动由CD4+T细胞做出的不同反应的假设。具体目标#2：验证Ly108控制小鼠树突状细胞、巨噬细胞和中性粒细胞杀菌机制的假设。具体目的#3：确定T细胞和吞噬细胞表面的Ly108在实验性结肠炎发病机制中的作用。 公共卫生相关性：该申请为旨在剖析细胞表面受体Ly108(Slamf6)如何控制炎症性肠病(IBD)发病机制中的适应性和先天免疫反应的研究寻求资金。对基因操纵的小鼠的研究，导致了一种理解，即免疫系统和结肠的巨大抗原量之间微调平衡的扰动会导致疾病。我们开始剖析T细胞是如何诱发或预防结肠炎的。然而，我们并不了解许多遗传和机制网络，这些网络参与了对结肠菌诱导的细菌抗原和/或小鼠抗原的先天和获得性免疫反应的调节。这些实验旨在检验这一普遍假设，即Ly108受体识别细菌，从而控制结肠炎的不同途径。拟议的实验结果应该能阐明Ly108在致病T细胞与巨噬细胞和中性粒细胞控制的实验性结肠炎途径之间相互作用的机制。这一结果应该为IBD患者提供可应用的治疗策略。

DESCRIPTION (provided by applicant): This application seeks funding for studies aimed at dissecting how the self-ligand cell surface receptor Ly108 (Slamf6) controls the adaptive and innate immune responses involved in the pathogenesis of experimental colitis. Studies with genetically well-defined mouse models of experimental IBD lead to an understanding that perturbations of the finely tuned balance between the immune system and the vast antigenic load of the colon results in disease. We are beginning to dissect how Treg cells prevent colitis, inducing pathogenic CD4+ T cells, e.g. Th1, Th2 or Th17, from expanding in the lamina propria. However, we do not understand many of the genetic and mechanistic networks that are implicated in the regulation of innate and adaptive immune responses to bacterial antigens and/or mouse antigens induced by colonic bacteria. Our general hypothesis is that the receptor isoforms encoded by the autoimmune gene Ly108, i.e. Ly108-1, Ly108-2 and Ly108-H1, govern distinct pathways to colitis. As our Preliminary Studies will demonstrate: i) engagement of Ly108 ameliorates colitis; ii) Ly108 governs distinct CD4+ T cell and NKT cell responses; and iii) Ly108 modulates responses to bacteria by macrophages or neutrophils, most likely because Ly108 enters phagosomes as a "scavenger-receptor". The fundamental strategy is to dissect the consequences of an imbalance of the three isoforms of Ly108 in T cell and phagocyte responses to commensal bacteria and in the pathogenesis of experimental colitis. We have the systems in place to employ our large series of novel genetically altered mice, our monoclonal antibodies, and soluble ligands to demonstrate the importance of receptor isoform interplay in disease manifestations. The proposed experiments are grouped into the following specific aims: Specific Aim #1: To test the hypothesis that the three isoforms of Ly108 initiate distinct responses by CD4+ T cells. Specific Aim #2: To test the hypothesis that Ly108 controls microbicidal mechanisms in mouse dendritic cells, macrophages and neutrophils. Specific Aim #3: To determine the role of Ly108 on the surface of T cells and phagocytes in the pathogenesis of experimental colitis. PUBLIC HEALTH RELEVANCE: This application seeks funding for studies aimed at dissecting how the cell surface receptor Ly108 (Slamf6) controls the adaptive and innate immune responses involved in the pathogenesis of Inflammatory Bowel Diseases (IBD). Studies with genetically manipulated mice, have led to an understanding that perturbations of the finely tuned balance between the immune system and the vast antigenic load of the colon results in disease. We are beginning to dissect how T cells induce or prevent colitis. However, we do not understand many of the genetic and mechanistic networks that are implicated in regulation of innate and adaptive immune responses to bacterial antigens and/or mouse antigens induced by colonic bacteria. The experiments are designed to test the general hypothesis is that Ly108 receptor recognizes bacteria and hence govern distinct pathways to colitis. The outcomes of the proposed experiments should clarify the mechanisms governed by Ly108 in the interplay between pathogenic T cells and macrophage- and neutrophil- controlled pathways to experimental colitis. The results with should suggest therapeutic strategies that can be applied to IBD patients.