bims-maitce 2024-10-27 papers

Issue of 2024–10–27
four papers selected by
Andy E. Hogan, Maynooth University

J Exp Med. 2025 Jan 06. pii: e20232298. [Epub ahead of print]222(1):

MAIT cells: Conserved watchers on the wall.

Lilou Germain, Pablo Veloso, Olivier Lantz, François Legoux.

MAIT cells are innate-like T cells residing in barrier tissues such as the lung, skin, and intestine. Both the semi-invariant T cell receptor of MAIT cells and the restricting element MR1 are deeply conserved across mammals, indicating non-redundant functions linked to antigenic specificity. MAIT cells across species concomitantly express cytotoxicity and tissue-repair genes, suggesting versatile functions. Accordingly, MAIT cells contribute to antibacterial responses as well as to the repair of damaged barrier tissues. MAIT cells recognize riboflavin biosynthetic pathway-derived metabolites, which rapidly cross epithelial barriers to be presented by antigen-presenting cells. Changes in gut ecology during intestinal inflammation drive the expansion of strong riboflavin and MAIT ligand producers. Thus, MAIT cells may enable real-time surveillance of microbiota dysbiosis across intact epithelia and provide rapid and context-dependent responses. Here, we discuss recent findings regarding the origin and regulation of MAIT ligands and the role of MAIT cells in barrier tissues. We speculate on the potential reasons for MAIT cell conservation during evolution.

DOI: https://doi.org/10.1084/jem.20232298

J Am Chem Soc. 2024 Oct 21.

Development of Ribityllumazine Analogue as Mucosal-Associated Invariant T Cell Ligands.

Ryosuke Takasaki, Emi Ito, Masamichi Nagae, Yuki Takahashi, Takuro Matsuoka, Wakana Yasue, Norihito Arichi, Hiroaki Ohno, Sho Yamasaki, Shinsuke Inuki.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the past decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found a chemically stable MAIT cell ligand with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The ligand showed high potency in a cocultivation assay using model cell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic analysis revealed the binding mode of the ligand to MR1 and the T cell receptor, indicating that it forms a covalent bond with MR1 via Schiff base formation. Furthermore, we found that the ligand stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed ligand is one of the most potent among chemically stable MAIT cell ligands, contributing to accelerating therapeutic applications of MAIT cells.

DOI: https://doi.org/10.1021/jacs.4c12997

Cells. 2024 Oct 16. pii: 1711. [Epub ahead of print]13(20):

Characterization of Tumor-Infiltrating Lymphocyte-Derived Atypical TCRs Recognizing Breast Cancer in an MR1-Dependent Manner.

Abdul Hayee, Eiji Kobayashi, Chihiro Motozono, Hiroshi Hamana, Ha Thi Viet My, Takuya Okada, Naoki Toyooka, Satoshi Yamaguchi, Tatsuhiko Ozawa, Hiroyuki Kishi.

The MHC class I-related 1 (MR1) molecule is a non-polymorphic antigen-presenting molecule that presents several metabolites to MR1-restricted T cells, including mucosal-associated invariant T (MAIT) cells. MR1 ligands bind to MR1 molecules by forming a Schiff base with the K43 residue of MR1, which induces the folding of MR1 and its reach to the cell surface. An antagonistic MR1 ligand, Ac-6-FP, and the K43A mutation of MR1 are known to inhibit the responses of MR1-restricted T cells. In this study, we analyzed MR1-restricted TCRs obtained from tumor-infiltrating lymphocytes (TILs) from breast cancer patients. They responded to two breast cancer cell lines independently from microbial infection and did not respond to other cancer cell lines or normal breast cells. Interestingly, the reactivity of these TCRs was not inhibited by Ac-6-FP, while it was attenuated by the K43A mutation of MR1. Our findings suggest the existence of a novel class of MR1-restricted TCRs whose antigen is expressed in some breast cancer cells and binds to MR1 depending on the K43 residue of MR1 but without being influenced by Ac-6-FP. This work provides new insight into the physiological roles of MR1 and MR1-restricted T cells.

Keywords: MR1; T-cell receptors; breast cancer; tumor-infiltrating lymphocytes

DOI: https://doi.org/10.3390/cells13201711

Front Oncol. 2024 ;14 1419528

Conserved allomorphs of MR1 drive the specificity of MR1-restricted TCRs.

Background: Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, was until recently considered to be monomorphic. MR1 presents metabolites in the context of host responses to bacterial infection. MR1-restricted TCRs specific to tumor cells have been described, raising interest in their potential therapeutic application for cancer treatment. The diversity of MR1-ligand biology has broadened with the observation that single nucleotide variants (SNVs) exist within MR1 and that allelic variants can impact host immunity.
Methods: The TCR from a MR1-restricted T-cell clone, MC.7.G5, with reported cancer specificity and pan-cancer activity, was cloned and expressed in Jurkat E6.1 TCRαβ- β2M- CD8+ NF-κB:CFP NFAT:eGFP AP-1:mCherry cells or in human donor T cells. Functional activity of 7G5.TCR-T was demonstrated using cytotoxicity assays and by measuring cytokine release after co-culture with cancer cell lines with or without loading of previously described MR1 ligands. MR1 allele sequencing was undertaken after the amplification of the MR1 gene region by PCR. In vivo studies were undertaken at Labcorp Drug Development (Ann Arbor, MI, USA) or Epistem Ltd (Manchester, UK).
Results: The TCR cloned from MC.7.G5 retained MR1-restricted functional cytotoxicity as 7G5.TCR-T. However, activity was not pan-cancer, as initially reported with the clone MC.7.G5. Recognition was restricted to cells expressing a SNV of MR1 (MR1*04) and was not cancer-specific. 7G5.TCR-T and 7G5-like TCR-T cells reacted to both cancer and healthy cells endogenously expressing MR1*04 SNVs, which encode R9H and H17R substitutions. This allelic specificity could be overcome by expressing supraphysiological levels of the wild-type MR1 (MR1*01) in cell lines.
Conclusions: Healthy individuals harbor T cells reactive to MR1 variants displaying self-ligands expressed in cancer and benign tissues. Described "cancer-specific" MR1-restricted TCRs need further validation, covering conserved allomorphs of MR1. Ligands require identification to ensure targeting MR1 is restricted to those specific to cancer and not normal tissues. For the wider field of immunology and transplant biology, the observation that MR1*04 may behave as an alloantigen warrants further study. .

Keywords: (TCR) T-cell receptor; MR1; T-cell; alloreactive; cancer

DOI: https://doi.org/10.3389/fonc.2024.1419528