MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-[alpha] chain

• Published in: The Journal of clinical investigation 2025-01, Vol.135 (1)
• Main Authors: Dolton, Garry, Thomas, Hannah, Tan, Li Rong, Rafael, Cristina Rius, Doetsch, Stephanie, Ionescu, Giulia-Andreea, Cardo, Lucia F, Crowther, Michael D, Behiry, Enas, Morin, Theo, Caillaud, Marine E, Srai, Devinder, Parolini, Lucia, Hasan, Md Samiul, Fuller, Anna, Topley, Katie, Wall, Aaron, Hopkins, Jade R, Omidvar, Nader, Alvares, Caroline, Zabkiewicz, Joanna, Frater, John, Szomolay, Barbara, Sewell, Andrew K
• Format: Article
• Language: English
• Subjects: Analysis; Antigen receptors, T cell; Cancer cells; Health aspects; Identification and classification; Receptors; T cells
• ISSN: 0021-9738
• DOI: 10.1172/JCI181895

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 mucosalassociated 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-[alpha] chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAVgenes and the TRAJ42 gene segment. This semi-invariance in the TCR-[alpha] chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.