GLP1R Strives T Cell Negative Costimulation Through a Rrna Gene Repressor Interactome

Glucagon Like Peptide-1 Receptor (GLP1R) is a key regulator of glucose metabolism, known to be expressed by pancreatic β-cells, gastric mucosa and hypothalamus. Recently, GLP1R mRNA has been detected on T lymphocytes; however, its function in these cells remains poorly understood. We herein investigated the role of GLP1R on T lymphocytes during immune response. Our data showed that a subset of naïve CD4 and CD8 T lymphocytes expresses GLP1R in humans and mice, while GLP1R appeared to have a unique interactome pattern in T lymphocytes different from those of pancreatic β-cells. Interestingly, the presence of GLP1R delineates a population of activated T cells which are more prone to cell death. GLP1R is upregulated in vitro and in vivo during alloimmune response, similarly to PD-1 and CTLA4. When C57BL/6 mice received islet or cardiac allotransplantation from a fully mismatched BALB/c donor, an expansion of GLP1R+ CD4+/CD8+ T cells occurred in the spleen and were found to infiltrate the graft. Importantly, when signaling through GLP1R with an agonist, T cell pathways of apoptosis and senescence are upregulated with significant prolongation of cardiac and islet allograft survival and reduced graft T lymphocytes infiltrate. The gene-repression protein Baz2a appeared to be responsible for driving the GLP1R-dependent T cell negative costimulation. Genetic GLP1R gain of function is associated with T cell activation and cell death, while GLP1RKO accelerate chronic allograft rejection. GLP1R acts as a T cell negative costimulatory molecule and GLP1R signaling prolongs allograft survival, mitigates alloimmune response and reduces T lymphocytes graft infiltration.