Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β 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 GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos 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 of colorectal cancer.
Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule / Ben Nasr, Moufida; Usuelli, Vera; Dellepiane, Sergio; Seelam, Andy Joe; Fiorentino, Teresa Vanessa; D'Addio, Francesca; Fiorina, Emma; Xu, Cong; Xie, Yanan; Balasubramanian, Hari Baskar; Castillo-Leon, Eduardo; Loreggian, Lara; Maestroni, Anna; Assi, Emma; Loretelli, Cristian; Abdelsalam, Ahmed; El Essawy, Basset; Uccella, Silvia; Pastore, Ida; Lunati, Maria Elena; Sabiu, Gianmarco; Petrazzuolo, Adriana; Ducci, Giacomo; Sacco, Elena; Centofanti, Lucia; Venturini, Massimo; Mazzucchelli, Serena; Mattinzoli, Deborah; Ikehata, Masami; Castellano, Giuseppe; Visner, Gary; Kaifeng, Liu; Lee, Kang Mi; Wang, Zhimin; Corradi, Domenico; La Rosa, Stefano; Danese, Silvio; Yang, Jun; Markmann, James F.; Zuccotti, Gian Vincenzo; Abdi, Reza; Folli, Franco; Fiorina, Paolo. - In: CELL METABOLISM. - ISSN 1550-4131. - 36:6(2024), pp. 1302-1319. [10.1016/j.cmet.2024.05.001]
Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule
Corradi, Domenico;
2024-01-01
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β 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 GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos 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 of colorectal cancer.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
