Recognition of MR1-antigen complexes by TCR Vγ9Vδ2

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

• University of Basel, Basel, Switzerland

The TCR-mediated activation of T cells expressing the TCR Vγ9Vδ2 relies on an innate-like mechanism involving the butyrophilin 3A1 and 2A1 molecules and phospho-antigens, without the participation of the TCR CDR3 regions or 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 butyrophilinindependent. 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.