AUTHOR=Loureiro José Pedro , Vacchini Alessandro , Berloffa Giuliano , Devan Jan , Schaefer Verena , Nosi Vladimir , Colombo Rodrigo , Beshirova Aisha , Montanelli Giulia , Meyer Benedikt , Sharpe Timothy , Chancellor Andrew , Recher Mike , Mori Lucia , De Libero Gennaro 

TITLE=Recognition of MR1-antigen complexes by TCR Vγ9Vδ2

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1519128

DOI=10.3389/fimmu.2025.1519128

ISSN=1664-3224

ABSTRACT=The TCR-mediated activation of T cells expressing the TCR Vγ9Vδ2 relies on an innate-like mechanism involving the butyrophilin 3A1, 3A2 and 2A1 molecules and phospho-antigens, without the participation of classical antigen-presenting molecules. Whether TCR Vγ9Vδ2 cells also recognize complexes composed of antigens and antigen-presenting molecules in an adaptive-like manner is unknown. Here, we identify MR1-autoreactive cells expressing the TCR Vγ9Vδ2. This MR1-restricted response is antigen- and CDR3δ-dependent and butyrophilin-independent. TCR gene transfer reconstitutes MR1-antigen recognition, and engineered TCR Vγ9Vδ2 tetramers interact with soluble MR1-antigen complexes in an antigen-dependent manner. These cells are present in healthy individuals with low frequency and are mostly CD8+ or CD4-CD8 double negative. We also describe a patient with autoimmune symptoms and TCR γδ lymphocytosis in which ~10% of circulating T cells are MR1-self-reactive and express a TCR Vγ9Vδ2. These cells release pro-inflammatory cytokines, suggesting a possible participation in disease pathogenesis. Thus, MR1-self-antigen complexes can interact with some TCRs Vγ9Vδ2, promoting full cell activation and potentially contributing to diseases.