Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1-restricted antimicrobial activity against Escherichia coli clinical strains in a manner dependent on the activity of cytolytic proteins but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to T cell receptor (TCR)-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living, extracellular forms of E. coli. Furthermore, MAIT cell-mediated bacterial control extends to multidrug-resistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli.

黏膜相关不变 T (MAIT) 细胞是人体中丰富的抗微生物 T 细胞，可识别源自 MHC-Ib 相关蛋白 (MR1) 呈递的微生物核黄素生物合成途径的抗原。然而，负责 MAIT 细胞抗菌活性的机制尚未完全了解，并且尚未探索这些机制对抗生素耐药细菌的功效。在这里，我们展示了 MAIT 细胞介导了 MR1 限制的对大肠杆菌的抗菌活性临床菌株以依赖于溶细胞蛋白的活性但不依赖于促炎细胞因子的产生或感染细胞凋亡诱导的方式。成孔抗微生物蛋白颗粒溶素和丝氨酸蛋白酶颗粒酶 B 的联合作用是响应 T 细胞受体 (TCR) 介导的对 MR1 呈递抗原的识别而释放的，对于介导对细胞相关和自由生活的控制至关重要，E 的细胞外形式。大肠杆菌。此外，MAIT细胞介导的细菌控制延伸到多重耐药性É。大肠杆菌主要的临床分离株还对碳青霉烯类（一类最后的抗生素）具有抗药性。值得注意的是，高含量的MAIT细胞secretomes颗粒溶素与粒酶B直接通过增加它们的渗透性，使最初损伤抗性细菌细胞ë。大肠杆菌对碳青霉烯类的杀菌活性敏感。这些研究结果确定溶细胞效应蛋白在MAIT细胞介导的抗菌活性的作用，并表明颗粒溶素和酶B增效恢复碳青霉烯类抗菌活性，克服碳青霉烯类耐药ë。大肠杆菌。