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Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation

View ORCID ProfileSara Suliman, Lars Kjer-Nielsen, Sarah K. Iwany, Kattya Lopez Tamara, Liyen Loh, Ludivine Grzelak, Katherine Kedzierska, Tonatiuh A. Ocampo, Alexandra J. Corbett, James McCluskey, Jamie Rossjohn, Segundo R León, Roger Calderon, Leonid Lecca Garcia, Megan B. Murray, D. Branch Moody, Ildiko Van Rhijn
doi: https://doi.org/10.1101/2021.03.25.436871
Sara Suliman
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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  • ORCID record for Sara Suliman
Lars Kjer-Nielsen
2Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Sarah K. Iwany
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Kattya Lopez Tamara
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
3Socios En Salud Sucursal Peru, Lima, Peru
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Liyen Loh
2Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
4Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Aurora, CO, USA
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Ludivine Grzelak
2Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Katherine Kedzierska
2Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Tonatiuh A. Ocampo
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Alexandra J. Corbett
2Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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James McCluskey
2Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Jamie Rossjohn
5Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
6Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
7Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
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Segundo R León
3Socios En Salud Sucursal Peru, Lima, Peru
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Roger Calderon
3Socios En Salud Sucursal Peru, Lima, Peru
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Leonid Lecca Garcia
3Socios En Salud Sucursal Peru, Lima, Peru
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Megan B. Murray
8Department of Global Health and Social Medicine, and Division of Global Health Equity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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D. Branch Moody
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Ildiko Van Rhijn
1Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
9Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584CL Utrecht, The Netherlands
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  • For correspondence: ivanrhijn@bwh.harvard.edu
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Abstract

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant T cell receptor (TCR) α chain that uses TRAV1-2 joined to TRAJ33/20/12 and recognize metabolites from bacterial riboflavin synthesis bound to the antigen-presenting molecule, MR1. Recently, our attempts to identify alternative MR1-presented antigens led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered antigen specificity is likely to lead to altered affinity for the most potent known antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), we performed bulk TCRα and β chain sequencing, and single cell-based paired TCR sequencing, on T cells that bound the MR1-5-OP-RU tetramer, but with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Whereas we initially interpreted these as diverse MR1-restricted TCRs, single cell TCR sequencing revealed that cells expressing atypical TCRα chains also co-expressed an invariant MAIT TCRα chain. Transfection of each non-TRAV1-2 TCRα chain with the TCRβ chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCRα chain expression in human T cells and competition for the endogenous β chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and non-canonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of antigen specificity.

Competing Interest Statement

LKN, AJC, JMcC, and JR are named co-inventors on patents describing MR1 tetramers. The MR1 tetramer technology was developed jointly by Prof. James McCluskey, Prof. Jamie Rossjohn, and Prof. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation
Sara Suliman, Lars Kjer-Nielsen, Sarah K. Iwany, Kattya Lopez Tamara, Liyen Loh, Ludivine Grzelak, Katherine Kedzierska, Tonatiuh A. Ocampo, Alexandra J. Corbett, James McCluskey, Jamie Rossjohn, Segundo R León, Roger Calderon, Leonid Lecca Garcia, Megan B. Murray, D. Branch Moody, Ildiko Van Rhijn
bioRxiv 2021.03.25.436871; doi: https://doi.org/10.1101/2021.03.25.436871
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Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation
Sara Suliman, Lars Kjer-Nielsen, Sarah K. Iwany, Kattya Lopez Tamara, Liyen Loh, Ludivine Grzelak, Katherine Kedzierska, Tonatiuh A. Ocampo, Alexandra J. Corbett, James McCluskey, Jamie Rossjohn, Segundo R León, Roger Calderon, Leonid Lecca Garcia, Megan B. Murray, D. Branch Moody, Ildiko Van Rhijn
bioRxiv 2021.03.25.436871; doi: https://doi.org/10.1101/2021.03.25.436871

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