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

iCD8α细胞作为介导肠道免疫的新型先天型淋巴细胞

• 批准号: 8858852
• 负责人: Luc Van Kaer
• 金额: $ 31.37万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858852
• 关键词: Affinity; Antibodies; Antigens; Bacteria; CD40 Antigens; Cells; Citrobacter rodentium; Colitis; Communicable Diseases; Cytokine Receptors; Cytoplasmic Granules; Development; Disease; Environment; Epithelial Cells; Gastrointestinal tract structure; Goals; IL7R gene; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-12; Interleukin-15; Intestines; Leukocytes; Ligands; Lymphocyte; Lymphocyte Subset; Lymphoid; Lymphoid Cell; MHC Class I Genes; MHC Class II Genes; Maps; Measures; Mediating; Methods; Modeling; Molecular Profiling; Morbidity - disease rate; Mucosal Immunity; Mus; Myelogenous; Names; Pathway interactions; Phagocytosis; Phenotype; Population; Preventive; Production; Property; Proteins; Research; Role; Signal Transduction; Sterility; Surface; System; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Tissues; Work; antigen processing; cell type; cytokine; cytotoxic; gastrointestinal infection; human subject; in vivo; intestinal epithelium; intraepithelial; microorganism; mortality; new therapeutic target; notch protein; novel; pathogen; progenitor; prophylactic; public health relevance; receptor; response; thymus-leukemia antigens

 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.

 描述（由申请人提供）：与肠上皮相关的免疫细胞包含多种可以影响胃肠道感染、肠道炎症和炎症性肠病的细胞群。我们最近发现了一种新型先天免疫细胞群，我们将其称为 iCD8a 细胞，在粘膜免疫中具有重要功能。 iCD8a 细胞驻留在肠上皮内，其特征是表达 CD8a 同二聚体。然而，这些细胞缺乏 TCR、NK1.1 和 IL-7Ra 表达，因此与上皮内淋巴细胞和先前鉴定的先天淋巴细胞亚群不同。我们的初步分析表明，这种新型免疫细胞群与免疫细胞的淋巴谱系比与骨髓谱系的关系更密切。此外，我们对 iCD8a 细胞的细胞因子表达谱和效应器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 的激动性抗体诱导的肠道炎症，以及肠道病原体啮齿类柠檬酸杆菌感染诱导的结肠炎。最后，我们发现人类受试者的肠上皮中存在与鼠 iCD8a 细胞表型相似的细胞。在这些初步研究的指导下，我们提出了最初的假设：iCD8a 细胞是一种新型的先天性淋巴群体，在胃肠道感染和炎症性疾病中具有调节作用。我们将测试这一假设的三个具体目标： 具体目标 1 将表征 iCD8a 细胞的谱系发育，以提供进一步的证据，证明这些细胞源自淋巴祖细胞，并且与之前描述的所有先天淋巴细胞亚群不同；具体目标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；具体目标 3 将评估 iCD8a 细胞对抗 CD40 抗体或啮齿类柠檬酸杆菌感染诱导的小鼠肠道炎症和结肠炎的影响。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。