Microbiology & Immunology - Research Publications

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Author: Godfrey, Dale × Author: Pellicci, Daniel × End date: 2022 × Start date: 2020 ×

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    CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells
    Souter, MNT ; Awad, W ; Li, S ; Pediongco, T ; Meehan, BS ; Meehan, LJ ; Tian, Z ; Zhao, Z ; Wang, H ; Nelson, A ; Le Nours, J ; Khandokar, Y ; Praveena, T ; Wubben, J ; Lin, J ; Sullivan, LC ; Lovrecz, G ; Mak, JYW ; Liu, L ; Kostenko, L ; Kedzierska, K ; Corbett, AJ ; Fairlie, DP ; Brooks, AG ; Gherardin, NA ; Uldrich, AP ; Chen, Z ; Rossjohn, J ; Godfrey, DI ; MCCLUSKEY, J ; Pellicci, DG ; Eckle, SBG (Rockefeller University Press, 2022)
    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.
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    CD36 family members are TCR-independent ligands for CD1 antigen-presenting molecules.
    Gherardin, NA ; Redmond, SJ ; McWilliam, HEG ; Almeida, CF ; Gourley, KHA ; Seneviratna, R ; Li, S ; De Rose, R ; Ross, FJ ; Nguyen-Robertson, CV ; Su, S ; Ritchie, ME ; Villadangos, JA ; Moody, DB ; Pellicci, DG ; Uldrich, AP ; Godfrey, DI (American Association for the Advancement of Science, 2021-06-25)
    CD1c presents lipid-based antigens to CD1c-restricted T cells, which are thought to be a major component of the human T cell pool. However, the study of CD1c-restricted T cells is hampered by the presence of an abundantly expressed, non-T cell receptor (TCR) ligand for CD1c on blood cells, confounding analysis of TCR-mediated CD1c tetramer staining. Here, we identified the CD36 family (CD36, SR-B1, and LIMP-2) as ligands for CD1c, CD1b, and CD1d proteins and showed that CD36 is the receptor responsible for non-TCR-mediated CD1c tetramer staining of blood cells. Moreover, CD36 blockade clarified tetramer-based identification of CD1c-restricted T cells and improved identification of CD1b- and CD1d-restricted T cells. We used this technique to characterize CD1c-restricted T cells ex vivo and showed diverse phenotypic features, TCR repertoire, and antigen-specific subsets. Accordingly, this work will enable further studies into the biology of CD1 and human CD1-restricted T cells.