Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
J Immunol. 2024 Jun 1;212(11):1843-1854. doi: 10.4049/jimmunol.2200556.
Intraepithelial lymphocytes (IELs) are T cells important for the maintenance of barrier integrity in the intestine. Colon IELs are significantly reduced in both MyD88-deficient mice and those lacking an intact microbiota, suggesting that MyD88-mediated detection of bacterial products is important for the recruitment and/or retention of these cells. Here, using conditionally deficient MyD88 mice, we show that myeloid cells are the key mediators of TCRαβ+ IEL recruitment to the colon. Upon exposure to luminal bacteria, myeloid cells produce sphingosine-1-phosphate (S1P) in a MyD88-dependent fashion. TCRαβ+ IEL recruitment may be blocked using the S1P receptor antagonist FTY720, confirming the importance of S1P in the recruitment of TCRαβ+ IELs to the colon epithelium. Finally, using the TNFΔARE/+ model of Crohn's-like bowel inflammation, we show that disruption of colon IEL recruitment through myeloid-specific MyD88 deficiency results in reduced pathology. Our results illustrate one mechanism for recruitment of a subset of IELs to the colon.
上皮内淋巴细胞 (IELs) 是 T 细胞，对于维持肠道屏障完整性很重要。MyD88 缺陷型小鼠和缺乏完整微生物群的小鼠的结肠 IELs 明显减少，这表明 MyD88 介导的细菌产物检测对于这些细胞的募集和/或保留很重要。在这里，我们使用条件性缺乏 MyD88 的小鼠表明，髓样细胞是 TCRαβ+ IEL 募集到结肠的关键介质。在暴露于腔细菌后，髓样细胞以依赖于 MyD88 的方式产生鞘氨醇-1-磷酸 (S1P)。使用 S1P 受体拮抗剂 FTY720 可以阻止 TCRαβ+ IEL 的募集，这证实了 S1P 在 TCRαβ+ IEL 募集到结肠上皮中的重要性。最后，我们使用克罗恩病样肠道炎症的 TNFΔARE/+ 模型表明，通过髓样细胞特异性 MyD88 缺陷破坏结肠 IEL 的募集会导致病理学减少。我们的结果说明了将一部分 IEL 募集到结肠的一种机制。
