TY - JOUR
T1 - CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells
AU - Souter, Michael N.T.
AU - Awad, Wael
AU - Li, Shihan
AU - Pediongco, Troi J.
AU - Meehan, Bronwyn S.
AU - Meehan, Lucy J.
AU - Tian, Zehua
AU - Zhao, Zhe
AU - Wang, Huimeng
AU - Nelson, Adam
AU - Le Nours, Jérôme
AU - Khandokar, Yogesh
AU - Praveena, T.
AU - Wubben, Jacinta
AU - Lin, Jie
AU - Sullivan, Lucy C.
AU - Lovrecz, George O.
AU - Mak, Jeffrey Y.W.
AU - Liu, Ligong
AU - Kostenko, Lyudmila
AU - Kedzierska, Katherine
AU - Corbett, Alexandra J.
AU - Fairlie, David P.
AU - Brooks, Andrew G.
AU - Gherardin, Nicholas A.
AU - Uldrich, Adam P.
AU - Chen, Zhenjun
AU - Rossjohn, Jamie
AU - Godfrey, Dale I.
AU - McCluskey, James
AU - Pellicci, Daniel G.
AU - Eckle, Sidonia B.G.
N1 - Funding Information:
We also would like to acknowledge the following funding: Australian Postgraduate Award (M.N.T. Souter), Australian Research Council (ARC) Discovery Early Career Research Award (DECRA) fellowship DE220101491 (W. Awad), ARC Future Fellowship FT160100074 (J. Le Nours), National Health and Medical Research Council (NHMRC) of Australia Leadership Investigator Grant 1173871 (K. Kedzierska), ARC Future Fellowship FT160100083 (A.J. Corbett), NHMRC Leadership Investigator Grant 1193745 (A.J. Corbett), Dame Kate Campbell Research Fellowship from The University of Melbourne (A.J. Corbett), NHMRC Leadership Investigator Grant 2009551 (D.P. Fairlie), NHMRC Leadership Investigator Grant 2008981 (J. Rossjohn), NHMRC Senior Principal Research Fellowship 1117766 and NHMRC Leadership Investigator Grant 2008913 (D.I. Godfrey), National Institutes of Health RO1 AI148407-01A1 (J. McCluskey, J. Rossjohn, D.P. Fairlie), ARC Centre of Excellence CE140100011 (J. Rossjohn, D.P. Fairlie, D.I. Godfrey), NHMRC Program Grant 1113293 (J. McCluskey, J. Rossjohn, D.I. Godfrey), CSL Centenary Fellowship (D.G. Pellicci), NHMRC Project Grant APP1144308 (D.G. Pellicci), NHMRC Project Grant APP1140126 (D.I. Godfrey, D.G.Pellicci), ARC DECRA fellowship DE170100407 (S.B.G. Eckle), NHMRC Project Grant APP1157388 (S.B.G. Eckle), 2019 Allergy and Immunology Foundation of Australasia research grant (S.B.G. Eckle), and NHMRC Emerging Leadership Investigator Grant 1196881 (S.B.G. Eckle).
Publisher Copyright:
© 2022 The University of Melbourne.
PY - 2022/9/5
Y1 - 2022/9/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137127317&partnerID=8YFLogxK
U2 - 10.1084/jem.20210828
DO - 10.1084/jem.20210828
M3 - Article
C2 - 36018322
AN - SCOPUS:85137127317
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
M1 - e20210828
ER -