CRTAM-CADM1 INTERACTION IN THE BIOLOGY OF GUT LYMPHOCYTES

 描述（由申请方提供）：遗传易感个体对微生物植物群的不适当免疫应答导致炎症性肠病（IBD）。IBD中的致病反应由CD 4 + TH 17驱动。预防或对抗IBD的免疫调节机制通常依赖于TdR和IL-10。然而，最近的研究已经确定了上皮内CD 4 + CD 8 +T细胞参与肠道炎症的调节。在这里，我们已经确定了肠T细胞上的CRTAM和肠DC上的CADM 1之间的新的分子相互作用，并证明了这种相互作用是稳态上皮内CD 4 + CD 8 +T细胞和T细胞增殖过程中TH 17应答所必需的。弓形虫感染这些结果要求进一步研究CRTAM-CADM 1相互作用对肠道免疫的影响及其对IBD治疗的潜在利用。在目的1中，我们提出了区分CRTAM-CADM 1相互作用是否：a）仅在肠粘膜中起作用以促进CD 4 +T细胞和CD 4 + CD 8 + T细胞的保留，或B）在肠系膜淋巴结中起作用以促进CD 4 +T细胞的引发和肠归巢分子的获得。目的2是基于无菌小鼠中不存在CD 4 + CD 8 + T细胞，而短链脂肪酸（SCFA）诱导其扩增的观察。因此，我们将研究微生物群诱导CD 4 + CD 8 +T细胞分化的机制，并询问这些机制是否涉及CRTAM-CADM 1相互作用。CD 4 + CD 8 +T细胞可能需要肠道CADM 1 +DCs呈递抗原。或者，肠道微生物群可能释放促进CD 4 + CD 8 +T细胞分化的代谢物，可能通过充当影响CD 4 + CD 8 +T细胞祖细胞或CADM 1 + DC的表观遗传学的组蛋白脱乙酰酶（HDAC）抑制剂。在目的3中，我们将探索CRTAM-CADM 1依赖性TH 17对T.弓形虫：我们将确定T.弓形虫感染是针对易位的宿主或特异于弓形虫。以及CRTAM-CADM 1的相互作用是否影响TH 17对一般的弓形虫的反应。鉴于CD 4 + CD 8 +T细胞在肠道免疫调节中的重要性，TH 17对自身免疫的反应的相关性以及操纵这些细胞用于治疗的需要，研究CRTAM-CADM 1相互作用的建议体现了肠道免疫的新视角，这是高度创新的，与IBD相关。

 DESCRIPTION (provided by applicant): An inappropriate immune response towards microbial flora in genetically predisposed individuals results in inflammatory bowel disease (IBD). The pathogenic response in IBD is driven by CD4+TH17. Immunoregulatory mechanisms that prevent or counter IBD typically rely on Tregs and IL-10. However, recent studies have identified the involvement of intraepithelial CD4+CD8+T cells in the regulation of intestinal inflammation. Here, we have identified a novel molecular interaction between CRTAM on intestinal T cells and CADM1 on intestinal DC and demonstrated that this interaction is required for intraepithelial CD4+CD8+T cells in the steady-state and for TH17 responses during T. gondii parasitic infection. These results mandate further investigation of the impact of CRTAM-CADM1 interactions on intestinal immunity and their potential exploitation for IBD therapy. In Aim 1, we propose experiments to distinguish whether CRTAM-CADM1 interactions act: a) exclusively in the gut mucosa to facilitate the retention of CD4+T cells and CD4+CD8+ T cells, or b) in the mesenteric lymph nodes to promote priming of CD4+T cells and the acquisition of gut homing molecules. Aim 2 is based on the observation that CD4+CD8+ T cells are absent in germ-free mice, whereas short chain fatty acids (SCFA) induce their expansion. Thus, we will investigate the mechanisms by which the microbiota induces the differentiation of CD4+CD8+T cells and ask whether these mechanisms involve CRTAM-CADM1 interaction. CD4+CD8+T cells may require presentation of commensal antigens by intestinal CADM1+DCs. Alternatively, commensal microbiota may release metabolites that facilitate CD4+CD8+T cell differentiation, possibly by acting as histone deacetylase (HDAC) inhibitors that impact the epigenetics of CD4+CD8+T cell progenitors or CADM1+DCs. In Aim 3, we will explore the mechanisms for the CRTAM-CADM1 dependency of TH17 responses to T. gondii: we will determine whether TH17 cells detected during T. gondii infection are directed toward translocated commensals or are specific for T. gondii and whether CRTAM-CADM1 interactions impact TH17 response to commensals in general. Given the emerging importance of CD4+CD8+T cells in the regulation of intestinal immunity, the relevance of TH17 responses to autoimmunity and the need to manipulate these cells for therapy, this proposal to study CRTAM-CADM1 interactions embodies a new perspective in intestinal immunity that is highly innovative and relevant to IBD.