CD4+ Tissue resident memory T-cells in Crohnâs Disease

摘要 克罗恩病（CD）是一种慢性病，发病率高，经济负担重。变异寄主 对生态失调的肠道微生物群的反应是CD发病机制的核心。根据这一概念， 与肠道微生物群密切相关的T细胞亚群，如Th17细胞，与CD密切相关。 虽然生物制剂已经改变了CD的临床管理，但> 50%的患者最终未能通过医疗 治疗和手术进展。因此，表征致病性T细胞途径对于开发是必要的 新的治疗方法，并确定CD的预后生物标志物。组织驻留记忆T细胞（TRM）是最近发现的一种 描述了组织限制性非循环记忆T细胞的子集。它们是抗原特异性的， 微生物负荷高的部位，包括肠道。这些特性使TRM成为链接的优秀候选者 具有异常宿主反应的肠道生态失调。事实上，我们已经报道了CD4 + TRM与致病性 与非炎性结肠炎相比，CD中的Th17特征在肠道中丰富，并且在CD中富集。 肠道疾病（IBD）对照。此外，这些富集的CD4 + TRM表达转录抑制因子PR， 锌指结构域（PRDM）1.反过来，用沉默RNA敲低PRDM1导致PRDM1表达上调。 关键细胞运输分子鞘氨醇1磷酸受体1（S1PR1）。根据定义，S1PR1是 在TRM中被抑制，这意味着PRDM1促进CD中致病性CD4 + TRM在肠中的保留。 通过转录控制细胞运输分子。此外，我们发现IL-15（其富含于 CD），通过CD4 + TRM促进炎性细胞因子的产生，类似于典型的促炎性细胞因子。 细胞因子IL-1 β和IL-23。最后，与CD中的生态失调驱动致病性 相对于非IBD，具有CD-微生物群的CD4 + TRM、人源化致菌性IL-10-/-小鼠发生严重结肠炎 控制微生物群定植的对应物。此外，这些组织中的大多数结肠炎性粘膜Th17细胞 小鼠带有TRM标记。因此，我们的数据表明CD微生物群诱导致病性CD 4 + TRM， 受PRDM1和IL-15调节。在此，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，和3）使用人源化的gnotobiotic小鼠 用来自CD患者和健康对照的微生物群定殖，定义CD微生物群 诱导致病性CD4 + TRM。

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.