Conserved allomorphs of MR1 drive specificity of MR1-restricted TCRs

Cornforth, T. V.; Moyo, N. A.; Cole, S.; Lam, E.; Lobry, T.; Wolchinsky, R.; Lloyd, A.; Ward, K.; Denham, E. M.; Besra, G. S.; Veerapen, N.; Illing, P. T.; Vivian, J. P.; Raynes, J. M.; Le Nours, J.; Purcell, A. W.; Kundu, S.; Silk, J. D.; Williams, L.; Papa, S.; Rossjohn, J.; Howie, D.; Dukes, J.

doi:10.1101/2023.07.17.548997

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bioRxiv · 10.1101/2023.07.17.548997

Conserved allomorphs of MR1 drive specificity of MR1-restricted TCRs

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Abstract

Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, has until recently been reported to be monomorphic. Tumor cell-specific MR1 restricted T cell receptors (TCRs) have been described, offering potential therapeutic application for cancer treatment. We show that human T cells expressing a TCR derived from an MR1-restricted T cell clone, termed MC.7.G5 (7G5.TCRT), retain MR1-directed cytotoxicity. However, activity is not pan-cancer, as initially reported with the clone MC.7.G5. Recognition is restricted by an allelic variant of MR1 (MR1*04) which is present at approximately 1% of the population at the heterozygote level. The 7G5 TCR is not cancer specific, as 7G5.TCRT and 7G5.TCRT-like TCRs react to both cancer and healthy cells expressing MR1*04 alleles. These data demonstrate that healthy individuals can harbor T cells reactive to an MR1 variant displaying self-ligands expressed in cancer and benign tissues. Targeting MR1 in cancer will require identification of cancer-specific presented ligands, and careful confirmation of cancer specificity of TCRs. MR1*04 may behave as an alloantigen warranting further study.

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Cornforth, T. V., Moyo, N. A., Cole, S., Lam, E., Lobry, T., Wolchinsky, R., Lloyd, A., Ward, K., Denham, E. M., Besra, G. S., Veerapen, N., Illing, P. T., Vivian, J. P., Raynes, J. M., Le Nours, J., Purcell, A. W., Kundu, S., Silk, J. D., Williams, L., Papa, S., Rossjohn, J., Howie, D., Dukes, J.. 2023-07-19. Conserved allomorphs of MR1 drive specificity of MR1-restricted TCRs. https://doi.org/10.1101/2023.07.17.548997

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