Classic costimulatory interactions in MAIT cell responses: from gene expression to immune regulation.

This article reviews the role of classic costimulatory interactions in regulating mucosa-associated invariant T (MAIT) cell responses, from gene expression to immune function. MAIT cells are innate-like T lymphocytes restricted by the monomorphic major histocompatibility complex-related protein 1 (MR1) that recognize microbial vitamin B metabolites and contribute to antimicrobial defense, cancer, autoimmunity, vaccine responses, and tissue repair. The review compares MAIT cells with conventional T cells regarding the expression and function of key costimulatory molecules from the immunoglobulin superfamily (e.g., CD28, ICOS) and the tumor necrosis factor (TNF)/TNF receptor superfamily (e.g., CD40 ligand, OX40, 4-1BB, CD27), highlighting their roles in MAIT cell development, activation, and effector functions. Transcriptomic analyses reveal differential expression patterns of these molecules in human peripheral blood and liver MAIT cells, and functional studies indicate that costimulatory pathways modulate MAIT cell cytokine production, cytotoxicity, and interactions with antigen-presenting cells and B cells. The authors emphasize the importance of understanding these costimulatory mechanisms to optimize MR1/MAIT cell-targeted immunotherapies and identify future research directions, including the impact of tissue microenvironments, MAIT cell subsets, and translational relevance from mouse models to humans.