Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule

Glucagon-like peptide -1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic b cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD -1. When mice received islet or cardiac allotransplantation, an expansion of GLP1R pos T cells occurred in the spleen and was found to infiltrate the graft. Additional single -cell sequencing (scRNA-seq) analysis conducted on GLP-1R pos and GLP-1R neg CD3 + T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1R pos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell -negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti -tumor immunity when tested in a preclinical mouse model colorectal cancer.