Study of LY108 innate and adaptive immune responses

描述（由申请人提供）：本申请为旨在剖析自配体细胞表面受体Ly108 （Slamf6）如何控制实验性结肠炎发病机制中涉及的适应性和先天免疫反应的研究寻求资助。对基因定义明确的实验性IBD小鼠模型的研究使人们认识到，免疫系统和结肠大量抗原负荷之间精细调节的平衡受到干扰会导致疾病。我们开始剖析Treg细胞如何通过诱导致病性CD4+ T细胞（如Th1、Th2或Th17）在固有层中扩张来预防结肠炎。然而，我们不了解许多涉及结肠细菌诱导的细菌抗原和/或小鼠抗原的先天和适应性免疫反应调节的遗传和机制网络。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。我们的初步研究将证明：i)使用Ly108改善结肠炎；ii) Ly108控制不同的CD4+ T细胞和NKT细胞反应；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”进入吞噬体。基本策略是剖析Ly108在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的三种异构体不平衡的后果。我们有合适的系统来利用我们大量的新型转基因小鼠，我们的单克隆抗体和可溶性配体来证明受体异构体相互作用在疾病表现中的重要性。提出的实验分为以下几个特定目的：特定目的#1：验证CD4+ T细胞对Ly108的三种亚型产生不同反应的假设。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微生物机制的假设。特异性目的#3：确定T细胞和吞噬细胞表面Ly108在实验性结肠炎发病机制中的作用。

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.