Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.
J Exp Med. 2022 Sep 5;219(9). doi: 10.1084/jem.20210828. Epub 2022 Aug 26.
Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)-related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8αα or CD8αβ coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8αα in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1-CD8αα, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8αα and CD8αβ enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8-MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8αα and CD8αβ act as functional coreceptors for MAIT and other MR1-reactive T cells.
黏膜相关不变 T（MAIT）细胞通过识别主要组织相容性复合体 I 类相关蛋白 1（MR1）呈递的基于核黄素的抗原来检测微生物感染。人类外周血中的大多数 MAIT 细胞表达 CD8αα 或 CD8αβ 核心受体，并且 MHC-I 分子上 CD8 的结合位点在 MR1 中相对保守。然而，没有直接证据表明 CD8 与 MR1 相互作用及其功能后果。同样，CD8αα 在淋巴细胞功能中的作用仍然定义不明确。在这里，我们使用新开发的在 CD8 结合位点处突变的 MR1 四聚体，并通过确定 MR1-CD8αα 的晶体结构，表明 CD8 与 MR1 结合，类似于它与 MHC-I 分子的结合。CD8αα 和 CD8αβ 增强了 MAIT 细胞对 MR1 的结合和细胞因子的产生。此外，CD8-MR1 相互作用对于其他 MR1 反应性 T 细胞识别叶酸衍生抗原至关重要。总之，我们的研究结果表明，CD8αα 和 CD8αβ 均可作为 MAIT 和其他 MR1 反应性 T 细胞的功能性共受体。
