Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Precision Medicine and Healthcare Research Centre, Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China.
Sci Adv. 2024 Jun 14;10(24):eadn6331. doi: 10.1126/sciadv.adn6331. Epub 2024 Jun 12.
Mucosal-associated invariant T (MAIT) cells are antimicrobial T cells abundant in the gut, but mechanisms for their migration into tissues during inflammation are poorly understood. Here, we used acute pediatric appendicitis (APA), a model of acute intestinal inflammation, to examine these migration mechanisms. MAIT cells were lower in numbers in circulation of patients with APA but were enriched in the inflamed appendix with increased production of proinflammatory cytokines. Using the patient-derived appendix organoid (PDAO) model, we found that circulating MAIT cells treated with inflammatory cytokines elevated in APA up-regulated chemokine receptors, including CCR1, CCR3, and CCR4. They exhibited enhanced infiltration of -pulsed PDAO in a CCR1-, CCR2-, and CCR4-dependent manner. Close interactions of MAIT cells with infected organoids led to the PDAO structural destruction and death. These findings reveal a previously unidentified mechanism of MAIT cell tissue homing, their participation in tissue damage in APA, and their intricate relationship with mucosal tissues during acute intestinal inflammation in humans.
黏膜相关不变 T（MAIT）细胞是大量存在于肠道中的抗微生物 T 细胞，但它们在炎症期间迁移到组织中的机制尚不清楚。在这里，我们使用小儿急性阑尾炎（APA）作为急性肠道炎症的模型，来研究这些迁移机制。患有 APA 的患者的循环中 MAIT 细胞数量减少，但在发炎的阑尾中丰富，促炎细胞因子的产生增加。使用源自患者的阑尾类器官（PDAO）模型，我们发现 APA 中升高的炎性细胞因子处理的循环 MAIT 细胞上调趋化因子受体，包括 CCR1、CCR3 和 CCR4。它们以 CCR1、CCR2 和 CCR4 依赖性方式增强了对-β 脉冲化 PDAO 的浸润。MAIT 细胞与感染的类器官的紧密相互作用导致 PDAO 结构破坏和死亡。这些发现揭示了 MAIT 细胞组织归巢的先前未被识别的机制，它们在 APA 中的组织损伤中的参与，以及它们在人类急性肠道炎症期间与黏膜组织的复杂关系。
