Background It is known that the mucosal-associated invariant T (MAIT) cells are the innate-like T cells that are restricted by the major histocompatibility complex-related molecule 1 (MR1), and that these cells express a semi-invariant T cell receptor. We have previously reported that the activation status of the circulating MAIT cells in patients with Ulcerative Colitis (UC) is associated with disease activity, and these cells infiltrate the inflamed colonic mucosa. These findings imply that MAIT cells are involved in the pathogenesis of Inflammatory Bowel Disease (IBD). However, the role of MAIT cells in the setting of IBD has not been revealed. Therefore, we investigated the role of MAIT cells in an animal model of UC. Methods To this end, we utilized MR1 deficient mice (MR1-/-), which lack MAIT cells, and isobutyl 6-formyl pterin (i6-FP), which is a synthetic antagonistic MR1 ligand. MR1-/- on the C57BL/6 background, their littermate wild-type controls, and C57BL/6 mice were sensitized by rectal administration of oxazolone to induce colitis. These were then administered an oral i6-FP. Splenocytes (SPL) and colonic lamina propria lymphocytes (LPL) were isolated from mice receiving i6-FP to measure cytokine production. MR1-/-, i6-FP-treated mice and their controls were orally administered FITC-dextran to analyze intestinal permeability. The peripheral blood mononuclear cells (PBMC) from the patients with UC were also isolated to study the effect of i6-FP on cytokine production by MAIT cells. Results MR1 deficiency or i6-FP treatment resulted in reduced severity of oxazolone-induced colitis. Mice treated with i6-FP resulted in reduced MAIT cell production of pro-inflammatory cytokines such as IFN-g and TNF in both SPL and colonic LPL. Similar results were also observed in PBMC isolated from the patients with UC when incubated with i6-FP. Although MR1 deficiency resulted in increased intestinal permeability, i6-FP administration did not affect gut integrity in mice. Conclusion The current studies indicate that MAIT cells have a pathogenic role in colitis and suppressing activation of these cells may reduce the severity of colitis without affecting gut integrity. Thus, MAIT cells may be potential therapeutic targets for IBD including UC.

中文翻译：

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P028 炎症性肠病动物模型中激活的粘膜相关不变 T 细胞的致病作用

背景已知粘膜相关不变T细胞（MAIT）是受主要组织相容性复合物相关分子1（MR1）限制的先天样T细胞，并且这些细胞表达半不变T细胞受体。我们之前曾报道，溃疡性结肠炎（UC）患者循环MAIT细胞的激活状态与疾病活动性相关，并且这些细胞浸润发炎的结肠粘膜。这些发现表明 MAIT 细胞参与炎症性肠病 (IBD) 的发病机制。然而，MAIT 细胞在 IBD 中的作用尚未被揭示。因此，我们研究了 MAIT 细胞在 UC 动物模型中的作用。方法为此，我们利用缺乏 MAIT 细胞的 MR1 缺陷小鼠 (MR1-/-) 和异丁基 6-甲酰蝶呤 (i6-FP)（一种合成的拮抗 MR1 配体）。通过直肠施用恶唑酮来致敏 C57BL/6 背景上的 MR1-/-、其同窝野生型对照和 C57BL/6 小鼠以诱导结肠炎。然后对这些患者进行口服 i6-FP。从接受 i6-FP 的小鼠中分离出脾细胞 (SPL) 和结肠固有层淋巴细胞 (LPL)，以测量细胞因子的产生。MR1-/-、i6-FP 处理的小鼠及其对照小鼠口服 FITC-葡聚糖来分析肠道通透性。还分离了 UC 患者的外周血单核细胞 (PBMC)，以研究 i6-FP 对 MAIT 细胞产生细胞因子的影响。结果 MR1 缺陷或 i6-FP 治疗可减轻恶唑酮诱导的结肠炎的严重程度。用 i6-FP 治疗的小鼠导致 MAIT 细胞在 SPL 和结肠 LPL 中产生促炎细胞因子（例如 IFN-g 和 TNF）减少。当与 i6-FP 孵育时，从 UC 患者分离的 PBMC 中也观察到类似的结果。尽管 MR1 缺陷导致肠道通透性增加，但 i6-FP 给药并不影响小鼠肠道完整性。结论 目前的研究表明，MAIT 细胞在结肠炎中具有致病作用，抑制这些细胞的激活可能会减轻结肠炎的严重程度，而不影响肠道完整性。因此，MAIT细胞可能是包括UC在内的IBD的潜在治疗靶点。