Diversity of T Cells Restricted by the MHC Class I-Related Molecule MR1 Facilitates Differential Antigen Recognition

Nicholas A Gherardin; Andrew N Keller; Rachel E Woolley; Jérôme Le Nours; David S Ritchie; Paul J Neeson; Richard W Birkinshaw; Sidonia B G Eckle; John N Waddington; Ligong Liu; David P Fairlie; Adam P Uldrich; Daniel G Pellicci; James McCluskey; Dale I Godfrey; Jamie Rossjohn

doi:10.1016/j.immuni.2015.12.005

Diversity of T Cells Restricted by the MHC Class I-Related Molecule MR1 Facilitates Differential Antigen Recognition

Immunity. 2016 Jan 19;44(1):32-45. doi: 10.1016/j.immuni.2015.12.005. Epub 2016 Jan 12.

Authors

Nicholas A Gherardin¹, Andrew N Keller², Rachel E Woolley², Jérôme Le Nours², David S Ritchie³, Paul J Neeson⁴, Richard W Birkinshaw², Sidonia B G Eckle⁵, John N Waddington⁶, Ligong Liu⁷, David P Fairlie⁷, Adam P Uldrich⁶, Daniel G Pellicci⁶, James McCluskey⁵, Dale I Godfrey⁸, Jamie Rossjohn⁹

Affiliations

¹ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia.
² Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
³ Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Department of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia.
⁴ Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
⁵ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
⁶ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia.
⁷ Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Queensland 4072, Australia.
⁸ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: [email protected].
⁹ Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: [email protected].

PMID: 26795251
DOI: 10.1016/j.immuni.2015.12.005

Abstract

A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2(+) T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative reactivity in a discrete subset of TRAV1-2(+) MAIT cells. This recognition was attributable to CDR3β loop-mediated effects within a consensus TRAV1-2(+) TCR-MR1-Ag footprint. Furthermore, we have demonstrated differential folate- and riboflavin-derivative reactivity by a diverse population of "atypical" TRAV1-2(-) MR1-restricted T cells. We have shown that TRAV1-2(-) T cells are phenotypically heterogeneous and largely distinct from TRAV1-2(+) MAIT cells. A TRAV1-2(-) TCR docks more centrally on MR1, thereby adopting a markedly different molecular footprint to the TRAV1-2(+) TCR. Accordingly, diversity within the MR1-restricted T cell repertoire leads to differing MR1-restricted Ag specificity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigen Presentation / immunology*
Autoimmunity / immunology
Crystallography, X-Ray
Flow Cytometry
Histocompatibility Antigens Class I / chemistry
Histocompatibility Antigens Class I / immunology*
Humans
Immunity, Mucosal / immunology
Jurkat Cells
Lymphocyte Activation / immunology*
Minor Histocompatibility Antigens
Receptors, Antigen, T-Cell / chemistry
Receptors, Antigen, T-Cell / immunology*
Surface Plasmon Resonance
T-Lymphocyte Subsets / immunology*
T-Lymphocytes / immunology*

Substances

Histocompatibility Antigens Class I
MR1 protein, human
Minor Histocompatibility Antigens
Receptors, Antigen, T-Cell