MR1 RECOGNITION BY HUMAN gd T CELLS
Jerome Le Nours, Monash University
Jérôme Le Nours 1,2, Nicholas A. Gherardin3,4, Victoria A. Hughes1,2, Andrew N. Keller1,2, Florian Wiede1, Benjamin S. Gully1,2, Richard Berry1,2, Maria L Sandoval-Romero 1, Shihan Li3,4, Sidonia B.G. Eckle3, Alexandra J. Corbett3, Ligong Liu5,6, David P. Fairlie5,6, Tony Tiganis1, James McCluskey3, Daniel G. Pellicci3,4, Adam P. Uldrich3,4, Dale I. Godfrey3,4 & Jamie Rossjohn1,2,7
1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
2. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
3. Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
4. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia
5. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; 6. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland 4072, Australia
7. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
The T lymphocytes repertoire is divided into two major lineages, αβ and γδ T cells, that are defined by their T cell receptor (TCR) gene-segment usage. The MHC-like molecule MR1 presents vitamin-B derivatives to mucosal-associated invariant T-cells. Using MR1 tetramers, we characterized a population of MR1-restricted human γδ T cells that included phenotypically diverse Vγ8-Vδ1, Vγ9-Vδ1 and Vγ8-Vδ3 subsets, all of which exhibited MR1 autoreactivity, independent on the nature of the bound ligand. The structure of a γδTCRMR1- antigen complex showed the γδTCR docked in a highly unusual manner that starkly contrasted all other TCR complex structures. The γδTCR bound perpendicular to MR1, clamping around one end of the MR1 antigen-binding cleft. Contacts were mediated exclusively by the TCR γ-chain and MR1, which included residues from the γδTCR constant domain. Accordingly, we define MR1 as a target for γδ T-cells and show that the γδTCR constant domain can contribute directly to antigen specificity. Our findings reshape our understanding of TCR recognition determinants and γδT-cells.