iCD8alpha cells as novel innate-type lymphoid cells that mediate gut immunity

 描述(申请人提供)：与肠道上皮相关的免疫细胞包括多种细胞群，可影响胃肠道感染、肠道炎症和炎症性肠病。我们最近发现了一种新的天然免疫细胞群，我们称之为iCD8a细胞，它在粘膜免疫中具有重要的功能。ICD8a细胞位于肠上皮细胞内，以表达CD8a同源二聚体为特征。然而，这些细胞缺乏TCR、NK1.1和IL-7ra的表达，因此不同于上皮内淋巴细胞和先前发现的天然淋巴样细胞亚群。我们的初步分析表明，这种新的免疫细胞群与免疫细胞的淋巴系比髓系系关系更密切。此外，我们对iCD8a细胞的细胞因子表达谱和效应功能的初步分析表明，它们属于免疫系统的先天分支。此外，我们还获得了初步证据表明，iCD8a细胞可以影响针对共刺激分子CD40的激动型抗体诱导的肠道炎症，以及由肠道病原体轮状柠檬酸杆菌感染引起的结肠炎。最后，我们发现在受试者的肠道上皮细胞中存在表型类似于小鼠iCD8a细胞的细胞。在这些初步研究的指导下，我们提出了最初的假设，即iCD8a细胞是一种新的先天类型淋巴组织，在胃肠道感染和炎症性疾病中具有调节作用。我们将验证这一假设有三个特定目的：特定目标1将表征iCD8a细胞的谱系发育，以提供进一步的证据，证明这些细胞来自淋巴祖细胞，不同于之前描述的所有固有淋巴细胞亚群；特定目标2将探索iCD8a细胞的效应功能，包括它们与粘膜上皮细胞和其他免疫细胞的相互作用；以及特定目标3将评估iCD8a细胞在抗CD40抗体或新冠杆菌感染诱导的小鼠肠道炎症和结肠炎中的作用。这项研究的长期目标是探索iCD8a细胞作为胃肠道感染性和炎症性疾病的新治疗靶点。

 DESCRIPTION (provided by applicant): Immune cells associated with the intestinal epithelium comprise a variety of cell populations that can influence gastrointestinal infections, intestinal inflammation and inflammatory bowel diseases. We have recently identified a novel innate immune cell population, which we have called iCD8a cells, with important functions in mucosal immunity. iCD8a cells reside within the intestinal epithelium and are characterized by expression of CD8a homodimers. However, these cells lack TCR, NK1.1 and IL-7Ra expression and are thus distinct from intraepithelial lymphocytes and previously identified subsets of innate lymphoid cells. Our preliminary analysis suggests that this novel immune cell population is more closely related to the lymphoid than the myeloid lineage of immune cells. Moreover, our initial analysis of the cytokine expression profile and effector functions of iCD8a cells indicates that they belong to the innate branch of the immune system. Additionally, we have obtained preliminary evidence that iCD8a cells can influence intestinal inflammation induced by agonistic antibodies directed against the co-stimulatory molecule CD40, and colitis induced by infection with the intestinal pathogen Citrobacter rodentium. Finally, we have shown the presence of cells with a phenotype similar to murine iCD8a cells in the intestinal epithelium of human subjects. Guided by these preliminary studies we have formulated the original hypothesis that iCD8a cells are a novel innate-type lymphoid population with a regulatory role in infections and inflammatory diseases of the gastrointestinal tract. We will test this hypothesis is three specific aims: Specifc Aim 1 will characterize the lineage development of iCD8a cells, to provide further evidence that these cells are derived from lymphoid progenitors and are distinct from all previously described innate lymphocyte subsets; Specific Aim 2 will explore the effector functions of iCD8a cells, including their interactions with mucosal epithelial cells and other immune cells; and Specific Aim 3 will assess the contribution of iCD8a cells to intestinal inflammation and colitis in mice induced by anti-CD40 antibodies or C. rodentium infection. The long-term goal of this research is to explore iCD8a cells as novel therapeutic targets for infectious and inflammatory disorders of the gastrointestinal tract.