Research ArticleImmunologyOncology Open Access | 10.1172/JCI181895

Garry Dolton,1 Hannah Thomas,1 Li Rong Tan,1 Cristina Rius Rafael,1 Stephanie Doetsch,1 Giulia-Andreea Ionescu,1 Lucia F. Cardo,1 Michael D. Crowther,1 Enas Behiry,1 Théo Morin,1 Marine E. Caillaud,1 Devinder Srai,2 Lucia Parolini,2 Md Samiul Hasan,1 Anna Fuller,1 Katie Topley,1 Aaron Wall,1 Jade R. Hopkins,1 Nader Omidvar,1 Caroline Alvares,3 Joanna Zabkiewicz,3 John Frater,4 Barbara Szomolay,1,5 and Andrew K. Sewell1,5,6

1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

Find articles by Szomolay, B. in: JCI | PubMed | Google Scholar |

1Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.

2Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.

3Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

4Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.

5Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.

6Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan.

Address correspondence to: Andrew K. Sewell, Cardiff University School of Medicine, Henry Wellcome Building, University Hospital Wales, Heath Park Campus, Cardiff CF14 4XN, Wales, United Kingdom. Phone: 44.29.2068.7055; Email: sewellak@cardiff.ac.uk.

Authorship note: GD and HT contributed equally to this work.

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Authorship note: GD and HT contributed equally to this work.

Published January 2, 2025 - More info

Published in Volume 135, Issue 1 on January 2, 2025
J Clin Invest. 2025;135(1):e181895. https://doi.org/10.1172/JCI181895.
© 2025 Dolton et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published January 2, 2025 - Version history
Received: April 11, 2024; Accepted: October 29, 2024 View PDF Abstract

The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosal-associated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1*01 and/or MR1*02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3–5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.

Graphical Abstract Introduction

Cytotoxic T lymphocytes (CTL), often called killer T cells, can destroy cells harboring intracellular pathogens or dysregulated gene expression associated with cancerous transformation. Classically, CTL express the CD8 glycoprotein and recognize processed proteinaceous antigens as short peptides of 8–14 amino acids in length presented by major histocompatibility complex class I (MHC-I) molecules (1). CD8 engages a largely invariant site on MHC-I to augment recognition of the peptide MHC by the highly variable αβ T cell receptor (TCR) (2, 3). More recent work has shown that some αβ T cells can recognize nonprotein, foreign, intracellular antigens presented by the CD1 family of proteins and MHC-related protein 1 (MR1), which also assemble with β2-microglobulin and adopt a highly similar fold and structure to MHC-I (4, 5). In humans CD1a, CD1b, CD1c, and CD1d are known to present different lipid antigens to T cells, whereas MR1 presents microbial metabolites to mucosal-associated invariant T (MAIT) cells (5, 6). MR1 has been conserved throughout mammalian evolution to an extent where human MAIT cells can cross react with murine MR1-presenting antigen (7, 8). MR1 is known to present vitamin B metabolites to MAIT cells and thereby signal that a self cell harbors an internal microbe (9, 10). The MAIT cell subset is characterized by a TCR-α chain that is made up of the TRAV1-2 gene in combination with a TRAJ33, TRAJ12, or TRAJ20-joining region (11). This semi-invariant TCR-α chain combines with a restricted number of TCR-β chains to severely limit MAIT cell TCR variability compared with αβ TCRs that recognize MHC-I (12, 13). Unlike human MHC-I, where there are over 10,000 different human leukocyte antigen class I (HLA-I) alleles across the human population (14), MR1 is far less variable with minimal amino acid differences, most of which are distal to the TCR docking site (15). A study of 56 samples with diverse HLA genotypes found 6 allele groups encoding for different but highly similar MR1 proteins. The vast majority of the study sample expressed either MR1*01 (71%) or MR1*02 (25%), which differ by encoding a histidine and an arginine at position 17, respectively, a position not thought to affect either antigen or TCR binding (15). Less than 3 amino acid substitutions were associated with the infrequent MR1*03 (I121V), MR1*04 (R9H, H17R), MR1*05 (E52G, H90Q, I244V), and MR1*06 (R304K) alleles. Of these substitutions, only R9H, present in MR1*04, is close to the known MR1 antigen binding site. Interestingly, a recent report described an individual who was homozygous for the R9H variant of MR1 that had a primary immunodeficiency and was found not to possess the MAIT cell subset (16). The R9H variant protein failed to present 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) to MAIT cells, providing a possible explanation for the lack of MAIT cells in this individual. It is not yet known whether other allelic variants of MR1 affect protein function or expression levels. Recent studies have shown that MR1 can present self antigens to MR1-restricted T cells (17) with a single MR1-restricted T cell being able to kill a wide range of cancer cell lines and primary cancer cells while remaining inert to healthy cells (18). The limited allelic variation of MR1 compared with HLA makes it an attractive target for potential cancer therapies. Here, we searched for cancer-activated, MR1-restricted T cell populations in 10 healthy donors and a patient with acute myeloid leukemia (AML). All donors possessed T cell populations that activated in response to MR1+ cancer cell lines but not MR1-KO lines. These T cells expressed CD8 and showed some dependency on lysine 43, which is known to form a Schiff base with bacterial MR1 ligands (19). TCR sequencing revealed a conserved TCR-α chain CAXYGGSQGNLIF (where X represents 3–5 amino acids) motif in 10 of 11 individuals that used the TRAJ42 gene that included the TRAJ42-encoded tyrosine residue at position 94–99, depending on TRAV gene usage. A similar conservation of TCR-α sequence, including a conserved Y95-α residue, is seen in MAIT cells (20), and suggests that TRAJ42+ cancer-activated invariant T cells are likely to see a common ligand.

Results

Generation of cancer-reactive MR1-restricted T cell lines and clones from multiple donors. We recently discovered an MR1-restricted T cell clone with an αβ TCR that allowed it to target a wide range of cancer cell lines and also control human leukemia cells in an NSG mouse model (18). Importantly, transfer of the TCR from this clone to the autologous CD8+ T cells from 2 patients with melanoma allowed these cells to lyse the patient’s own tumor line (18). This finding has garnered interest in exploring MR1-mediated options for immunotherapy due to the substantially lower variability of MR1 across the population compared with HLA (21, 22) (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI181895DS1). We set out to generate further T cell clones that responded to cancer lines via MR1 to determine whether most donors had T cells with this property. Our catch-all strategy to generate cancer-specific MR1-restricted T cells is outlined in Figure 1A and involved T cell priming from the PBMC of 3 donors using C1R cells (MR1*01+/+) overexpressing MR1*01. After the initial priming, 2 of 3 donors had T cells reactive toward overexpressed MR1 on either C1R or melanoma cells, but no MR1-restricted reactivity with WT melanoma cells (Figure 1B). These primed T cells were then enriched following exposure to WT melanoma line MM909.24 or MR1-KO MM909.24 overexpressing MR1*01 and expanded for 2 weeks prior to testing. Two of the lines enriched with MM909.24 overexpressing MR1*01 responded well to these targets but exhibited dependency on overexpressed MR1*01 for maximal reactivity, with minimal activation toward WT melanoma cells (Figure 1C). In contrast, the lines from all 3 donors that were enriched with WT MM909.24 displayed similar reactivity to WT MM909.24 and MR1*01 overexpressed cells, while not responding to MM909.24 MR1–/– targets (Figure 1C). These experiments show that it is possible to culture T cells that recognize a WT melanoma cell line via the MR1 molecule from all donors tested. We next aimed to characterize these T cells and the TCRs they express.

Figure 1

Induction of T cells reactive to natural levels of MR1 on the surface of cancer cells. (A) PBMCs from healthy donors were primed for 2 weeks with C1R cells overexpressing MR1*01. Primed T cells were enriched for reactivity toward WT melanoma,or MR-KO (–/–) melanoma cells overexpressing MR1*01, using TNF capture antibody and magnetic beads. The captured T cells were expanded for 2 weeks with irradiated PBMCs and PHA before analysis. (B) Three donors primed for 2 weeks with C1R cells overexpressing MR1*01 then tested against C1R and melanoma MM909.24 cells, indicated on the x-axis. Intracellular cytokine staining (ICS) was performed with CD107a and TNF antibodies. (C) The primed lines from B were coincubated with WT melanoma MM909.24 or MR1-KO melanoma MM909.24 overexpressing MR1*01, then reactive T cells captured based on TNF secretion and magnetic sorting. T cells enriched with the melanoma overexpressing MR1*01 (pink) preferred the overexpressed cell line (red box), whereas the T cells enriched with WT melanoma (yellow) gave similar MR1-dependent reactivity for both the WT and MR1 overexpressing melanoma (red box). ICS was performed with CD107a and TNF antibodies.

Characterization of MR1-restricted melanoma reactive T cells. We succeeded in isolating an MR1-restricted T cell clone from Donor 0, called MC.27.759S, which grew sufficiently in culture to allow us to make comparisons with the previously described T cell clone MC.7.G5 (18). MC.27.759S and MC.7.G5 both killed A549 WT (MR1*01/*04) lung cancer cells but failed to kill these cells when MR1 was knocked out using CRISPR technology (23) (