MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain.
| Title: | MHC-related protein 1-restricted recognition of cancer via a semi-invariant TCR-α chain. |
|---|---|
| Authors: | Dolton G; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Thomas H; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Tan LR; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Rius Rafael C; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Doetsch S; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Ionescu GA; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Cardo LF; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Crowther MD; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Behiry E; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Morin T; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Caillaud ME; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Srai D; Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.; Parolini L; Nuffield Department of Medicine and Department of Chemistry, University of Oxford, Oxford, United Kingdom.; Hasan MS; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Fuller A; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Topley K; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Wall A; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Hopkins JR; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Omidvar N; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Alvares C; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.; Zabkiewicz J; Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.; Frater J; Nuffield Department of Medicine and NIHR Biomedical Research Centre University of Oxford, Oxford, United Kingdom.; Szomolay B; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.; Sewell AK; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.; Systems Immunology Research Institute, Cardiff University Cardiff, United Kingdom.; Division of Infection and Immunity, Kumamoto University, Kumamoto, Japan. |
| Source: | The Journal of clinical investigation [J Clin Invest] 2025 Jan 02; Vol. 135 (1). Date of Electronic Publication: 2025 Jan 02. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation; Original Publication: New Haven [etc.] American Society for Clinical Investigation. |
| MeSH Terms: | Minor Histocompatibility Antigens*/genetics ; Minor Histocompatibility Antigens*/immunology ; Minor Histocompatibility Antigens*/metabolism ; Histocompatibility Antigens Class I*/immunology ; Histocompatibility Antigens Class I*/genetics ; Histocompatibility Antigens Class I*/metabolism ; Neoplasms*/immunology ; Neoplasms*/genetics ; Neoplasms*/metabolism; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/immunology ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Mucosal-Associated Invariant T Cells/immunology ; Mucosal-Associated Invariant T Cells/metabolism ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Humans ; Antigen Presentation ; Amino Acid Motifs ; Cell Line, Tumor |
| 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. |
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| Grant Information: | BB/H001085/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; CGCATF-2021/100014 United Kingdom CRUK_ Cancer Research UK |
| Contributed Indexing: | Keywords: Cancer; Cellular immune response; Immunology; Oncology; T cells |
| Substance Nomenclature: | 0 (Minor Histocompatibility Antigens); 0 (Histocompatibility Antigens Class I); 0 (MR1 protein, human); 0 (Receptors, Antigen, T-Cell, alpha-beta); 0 (Antigens, Neoplasm) |
| Entry Date(s): | Date Created: 20250102 Date Completed: 20250102 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11684821 |
| DOI: | 10.1172/JCI181895 |
| PMID: | 39744940 |
| Database: | MEDLINE |
Journal Article