Vorkas Charles Kyriakos, Levy Olivier, Skular Miroslav, Li Kelin, Aubé Jeffrey, Glickman Michael S
Division of Infectious Diseases, Weill Cornell Medicine, Cornell University, New York, New York, USA.
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Infect Immun. 2020 Dec 15;89(1). doi: 10.1128/IAI.00524-20.
Mucosa-associated invariant T (MAIT) cells are an innate-like T cell subset in mammals that recognize microbial vitamin B metabolites presented by the evolutionarily conserved major histocompatibility complex class I (MHC I)-related molecule, MR1. Emerging data suggest that MAIT cells may be an attractive target for vaccine-induced protection against bacterial infections because of their rapid cytotoxic responses at mucosal services to a widely conserved bacterial ligand. In this study, we tested whether a MAIT cell priming strategy could protect against aerosol infection in mice. Intranasal costimulation with the lipopeptide Toll-like receptor (TLR)2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in the lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early after challenge, these MAIT cells did not restrict bacterial load. MAIT cells were depleted by the onset of the adaptive immune response, with decreased detection of granzyme B and gamma interferon (IFN-γ) MAIT cells relative to that in uninfected P2C/5-OP-RU-treated mice. Decreasing the infectious inoculum, varying the time between priming and aerosol infection, and testing MAIT cell priming in nitric oxide synthase 2 (NOS2)-deficient mice all failed to reveal an effect of P2C/5-OP-RU-induced MAIT cells on control. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion after exposure, without attenuating growth, suggesting that MAIT cell enrichment in the lung is not sufficient to control infection.
黏膜相关恒定T（MAIT）细胞是哺乳动物中一类固有样T细胞亚群，可识别由进化上保守的主要组织相容性复合体I类（MHC I）相关分子MR1呈递的微生物维生素B代谢产物。新出现的数据表明，MAIT细胞可能是疫苗诱导预防细菌感染的一个有吸引力的靶点，因为它们在黏膜部位对广泛保守的细菌配体具有快速的细胞毒性反应。在本研究中，我们测试了一种MAIT细胞启动策略是否能保护小鼠免受气溶胶感染。用脂肽Toll样受体（TLR）2/6激动剂Pam2Cys（P2C）和合成MR1配体5-OP-RU进行鼻内共刺激，导致肺中MAIT细胞大量扩增。尽管MAIT细胞启动在攻击后早期显著增强了MAIT细胞的活化和扩增，但这些MAIT细胞并未限制细菌载量。随着适应性免疫反应的开始，MAIT细胞被耗尽，与未感染的P2C/5-OP-RU处理小鼠相比，颗粒酶B和γ干扰素（IFN-γ）MAIT细胞的检测减少。降低感染接种量、改变启动与气溶胶感染之间的时间间隔以及在一氧化氮合酶2（NOS2）缺陷小鼠中测试MAIT细胞启动，均未能揭示P2C/5-OP-RU诱导的MAIT细胞对感染控制的影响。我们得出结论，小鼠鼻内MAIT细胞启动在暴露后诱导早期MAIT细胞活化和扩增，但不减弱细菌生长，这表明肺中MAIT细胞的富集不足以控制感染。
