Oral Presentation CD1-MR1 2024

Adaptive MR1T cells recognise self-metabolites (#47)

Andrew Chancellor 1 , Qinmei Yang 1 , Daniel Constantin 1 , Giuliano Berloffa 1 , Vladimir Nosi 1 , Rodrigo Colombo 1 , Roman Jakob 1 , J. Pedro Loureiro 1 , Daniel Joss 1 , Michael Pfeffer 1 , Verena Schäfer 1 , Alessandro Vacchini 1 , Giulia Di Simone 2 , Aurelia Morabito 2 , Laura Brunelli 2 , Alfred Zippelius 1 , Enrico Davoli 2 , Daniel Häussinger 1 , Timm Maier 1 , Lucia Mori 1 , Gennaro De Libero 1
  1. Basel University, Basel, BASEL-STADT, Switzerland
  2. Department of Environmental Health Science, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

MR1 presents altered metabolites to T cells. The capacity of the immune system to surveil cellular metabolic integrity opens a new paradigm in immunology. Thus, a detailed understanding of the MR1-restricted T cell repertoire is required. We identified a cell endogenous carbonyl-adduct of adenine, 8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde (M3Ade) that is presented by MR1 to T cells. Structural analysis showed that it binds in the A' pocket of MR1 via a Schiff base. We generated MR1-M3Ade tetramers to identify and isolate reactive MR1T cells, which were polyfunctional and broadly reactive to different healthy and tumour cell types. Single cell-sequencing and high-dimensional flow cytometry revealed that MR1T cells display features of adaptive T cells, following a functional differentiation pathway from naïve to recently activated and then to memory or effector cells. Some MR1T cells are expanded in vivo, indicating their Ag experience. These data suggest that MR1T cells are involved in surveilling metabolic alterations in healthy and cancer cells. Their physiological functions and contribution to diseases are yet to be understood.