CD4+ Tissue resident memory T-cells in Crohn's Disease

克罗恩病中的 CD4 组织驻留记忆 T 细胞

• 批准号: 10054822
• 负责人: Shrinivas Bishu
• 金额: $ 17.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10054822
• 关键词: Affect; Antigens; Biological; Biometry; CD6 antigen; CD8B1 gene; Caring; Case Series; Cells; ChIP-seq; Characteristics; Chronic; Clinical Management; Colitis; Crohn' s disease; Data; Dendritic Cells; Disease Outcome; Disease remission; Economic Burden; Economics; Exhibits; FCGR3B gene; Genes; Gnotobiotic; Goals; Immune response; Immunohistochemistry; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-15; Intestines; Lead; Link; Maintenance; Medical; Memory; Methods; Morbidity - disease rate; Mucous Membrane; Mus; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Population; Production; Prognostic Marker; RNA Interference; Recurrence; Regulation; Reporting; Residencies; Role; Signal Pathway; Site; Small Interfering RNA; Source; Sphingosine-1-Phosphate Receptor; T cell therapy; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Training; Transcription Repressor; Transcriptional Regulation; Up-Regulation; Ursidae Family; Validation; Zinc Fingers; cytokine; disorder control; drug development; dysbiosis; effective therapy; enteric dysbiosis; gut microbiota; imprint; in vitro Assay; in vivo; interleukin-23; knock-down; memory retention; microbial; microbiota; new therapeutic target; novel; novel therapeutics; receptor; trafficking; translational study

ABSTRACT Crohn’s disease (CD) is a chronic condition with high morbidity and economic burden. Aberrant host responses to dysbiotic enteric microbiota are central to the pathogenesis of CD. Consistent with this concept, T-cell subsets closely aligned with the enteric microbiota, such as Th17 cells, are strongly implicated in CD. Although biologics have transformed the clinical management of CD, > 50% of patients eventually fail medical therapies and progress to surgery. Thus, characterizing pathogenic T-cell pathways is necessary to develop new therapies and identify prognostic biomarkers in CD. Tissue-resident memory T-cells (TRM) are a recently described subset of tissue-restricted non-circulating memory T-cells. They are antigen-specific and enriched at sites with high microbial burden, including the intestine. These features make TRM excellent candidates to link enteric dysbiosis with aberrant host responses. Indeed, we have reported that CD4+ TRM with a pathogenic Th17 signature are abundant in the intestine in CD and are enriched in CD compared to non-Inflammatory Bowel Disease (IBD) controls. Moreover, these enriched CD4+ TRM express the transcriptional repressor PR zinc finger domain (PRDM)1. In turn, knockdown of PRDM1 with silencing RNA results in the upregulation of the key cell trafficking molecule sphingosine 1 phosphate receptor 1 (S1PR1). As S1PR1 is by definition suppressed in TRM, this implies that PRDM1 promotes retention of pathogenic CD4+ TRM in the intestine in CD via transcriptional control of cell trafficking molecules. Furthermore, we find that IL-15 (which is enriched in CD), promotes the production of inflammatory cytokines by CD4+ TRM similar to the canonical pro-inflammatory cytokines IL-1β and IL-23. Finally, compatible with the possibility that the dysbiosis in CD drives pathogenic CD4+ TRM, humanized gnotobiotic IL-10-/- mice with CD-microbiota develop severe colitis relative to non-IBD control microbiota colonized counterparts. Moreover, the majority of colitogenic mucosal Th17 cells in these mice bear TRM markers. Thus, our data indicate that the CD microbiota induced pathogenic CD4+ TRM, which are regulated by PRDM1 and IL-15. Herein, we propose to 1) determine the mechanism and predictive capacity of PRDM1 in CD, 2) delineate the role of IL-15 in CD4+ TRM and 3) using humanized gnotobiotic mice colonized with microbiota from CD patients and healthy controls, define the extent to which CD microbiota induces pathogenic CD4+ TRM.

摘要 克罗恩病(CD)是一种发病率高、经济负担大的慢性疾病。变态宿主 对肠道微生物区系的不良反应是CD发病机制的核心。与这一概念相一致， 与肠道微生物区系关系密切的T细胞亚群，如Th17细胞，与CD密切相关。 尽管生物制剂改变了CD的临床治疗，但50%的患者最终未能通过医疗检查 治疗和手术的进展。因此，确定致病T细胞途径的特征是发展的必要 新的治疗方法和CD中的预后生物标记物。组织驻留记忆T细胞(TRM)是近年来发展起来的一种 描述了组织受限的非循环记忆T细胞的子集。它们是抗原特异性的，并在 微生物负荷高的地方，包括肠道。这些功能使TRM成为链接的优秀候选者 肠道菌群失调伴有异常的宿主反应。事实上，我们已经报道了CD4+TRM与一种致病性 Th17信号在CD的肠道中丰富，与非炎症性疾病相比，CD中的T17信号丰富 肠道疾病(IBD)对照。此外，这些富含的CD4+TRM表达转录抑制因子PR 锌指结构域(PRDM)1。反过来，沉默RNA敲除PRDM1导致其上调 关键的细胞运输分子鞘氨醇1磷酸受体1(S1PR1)。因为根据定义，S1PR1 在TRM中被抑制，这意味着PRDM1促进CD致病的CD4+TRM在肠道中的滞留 通过对细胞运输分子的转录控制。此外，我们发现IL-15(富含在 CD)，通过与典型的促炎作用类似的CD4+TRM促进炎性细胞因子的产生 细胞因子IL-1、β和IL-23。最后，与CD中的生物失调导致致病的可能性相一致 与非IBD相比，具有CD-微生物区系的人源化灵知生菌IL-10-/-小鼠发生严重结肠炎 控制微生物区系定植的对应物。此外，这些组织中的大多数结肠性粘膜Th17细胞 小鼠带有TRM标记。因此，我们的数据表明，CD微生物区系诱导了致病的CD4+TRM，这 受PRDM1和IL-15调节。在这里，我们建议1)确定机制和预测 PRDM1在CD中的能力，2)描述IL-15在CD4+TRM中的作用，3)利用人源化的GnotoBiotic小鼠 被CD患者和健康对照组的微生物群定植，定义了CD微生物群的程度 诱导致病的CD4+TRM。