Glucagon Like Peptide-1 Receptor (GLP1R) is a key regulator of glucose metabolism, known to be expressed by pancreatic β-cells, gastric mucosa and hypothalamic appetite center. Recently, GLP1R mRNA has been detected on T lymphocytes; however, its function in these cells remains poorly understood. We herein investigated the extent of GLP1R expression in T lymphocytes and the role of its signalling during alloimmune response. Our data showed that, a subset of naïve CD4 and CD8 lymphocytes expresses GLP1R in humans and mice. When C57BL/6 mice received islet or cardiac allotransplantation from a fully mismatched BALB/c donors, an expansion of GLP1R+ CD4+/CD8+ cells occurred in the spleen and were found to infiltrate the graft at high percentage. Interestingly, the treatment with the GLP1R agonist Exenatide significantly prolonged cardiac and islet allograft survival and reduced graft T lymphocytes infiltrate. Interestingly, a strong synergism in mitigating alloimmunity was observed between Exenatide and Rapamycin. Mechanistically, mitogen stimulated CD4+GLP1R+ and CD8+ GLP1R+ T cells, showed significantly more cell death as compared to controls. Notably, our transcriptomic data on GLP1R+CD4+ and GLP1R+CD8+ T cells revealed/confirmed their tendency toward an apoptotic/anergic profile as compared to their counterparts untreated. In conclusion, GLP1R appeared to act as a negative costimulatory molecule and the GLP1R agonist Exenatide prolongs allograft survival, mitigates alloimmunity during alloimmune response, reduces T lymphocytes graft infiltration and skews the effector/regulatory T cell balance.

GLP1R IS A T CELL NEGATIVE COSTIMULATORY MOLECULE / A.j. Seelam ; tutor: G. V. Zuccotti ; coordinatore: L. Pinotti. Dipartimento di Scienze Biomediche e Cliniche, 2023 Mar 30. 35. ciclo, Anno Accademico 2022.

GLP1R IS A T CELL NEGATIVE COSTIMULATORY MOLECULE

A.J. Seelam
2023

Abstract

Glucagon Like Peptide-1 Receptor (GLP1R) is a key regulator of glucose metabolism, known to be expressed by pancreatic β-cells, gastric mucosa and hypothalamic appetite center. Recently, GLP1R mRNA has been detected on T lymphocytes; however, its function in these cells remains poorly understood. We herein investigated the extent of GLP1R expression in T lymphocytes and the role of its signalling during alloimmune response. Our data showed that, a subset of naïve CD4 and CD8 lymphocytes expresses GLP1R in humans and mice. When C57BL/6 mice received islet or cardiac allotransplantation from a fully mismatched BALB/c donors, an expansion of GLP1R+ CD4+/CD8+ cells occurred in the spleen and were found to infiltrate the graft at high percentage. Interestingly, the treatment with the GLP1R agonist Exenatide significantly prolonged cardiac and islet allograft survival and reduced graft T lymphocytes infiltrate. Interestingly, a strong synergism in mitigating alloimmunity was observed between Exenatide and Rapamycin. Mechanistically, mitogen stimulated CD4+GLP1R+ and CD8+ GLP1R+ T cells, showed significantly more cell death as compared to controls. Notably, our transcriptomic data on GLP1R+CD4+ and GLP1R+CD8+ T cells revealed/confirmed their tendency toward an apoptotic/anergic profile as compared to their counterparts untreated. In conclusion, GLP1R appeared to act as a negative costimulatory molecule and the GLP1R agonist Exenatide prolongs allograft survival, mitigates alloimmunity during alloimmune response, reduces T lymphocytes graft infiltration and skews the effector/regulatory T cell balance.
30-mar-2023
Settore MED/13 - Endocrinologia
ZUCCOTTI, GIAN VINCENZO
PINOTTI, LUCIANO
Doctoral Thesis
GLP1R IS A T CELL NEGATIVE COSTIMULATORY MOLECULE / A.j. Seelam ; tutor: G. V. Zuccotti ; coordinatore: L. Pinotti. Dipartimento di Scienze Biomediche e Cliniche, 2023 Mar 30. 35. ciclo, Anno Accademico 2022.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/959499
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