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

Moufida Ben Nasr; Vera Usuelli; Sergio Dellepiane; Andy Joe Seelam; Teresa Vanessa Fiorentino; Francesca D'Addio; Emma Fiorina; Cong Xu; Yanan Xie; Hari Baskar Balasubramanian; Eduardo Castillo-Leon; Lara Loreggian; Anna Maestroni; Emma Assi; Cristian Loretelli; Ahmed Abdelsalam; Basset El Essawy; Silvia Uccella; Ida Pastore; Maria Elena Lunati; Gianmarco Sabiu; Adriana Petrazzuolo; Giacomo Ducci; Elena Sacco; Lucia Centofanti; Massimo Venturini; Serena Mazzucchelli; Deborah Mattinzoli; Masami Ikehata; Giuseppe Castellano; Gary Visner; Liu Kaifeng; Kang Mi Lee; Zhimin Wang; Domenico Corradi; Stefano La Rosa; Silvio Danese; Jun Yang; James F. Markmann; Gian Vincenzo Zuccotti; Reza Abdi; Franco Folli; Paolo Fiorina

doi:10.1016/j.cmet.2024.05.001

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

Moufida Ben Nasr
, Vera Usuelli
, Sergio Dellepiane
, Andy Joe Seelam
, Teresa Vanessa Fiorentino
, Francesca D'Addio
, Emma Fiorina
, Cong Xu
, Yanan Xie
, Hari Baskar Balasubramanian
, Eduardo Castillo-Leon
, Lara Loreggian
, Anna Maestroni
, Emma Assi
, Cristian Loretelli
, Ahmed Abdelsalam
, Basset El Essawy
, Silvia Uccella
, Ida Pastore
, Maria Elena Lunati

Gianmarco Sabiu, Adriana Petrazzuolo, Giacomo Ducci, Elena Sacco, Lucia Centofanti, Massimo Venturini, Serena Mazzucchelli, Deborah Mattinzoli, Masami Ikehata, Giuseppe Castellano, Gary Visner, Liu Kaifeng, Kang Mi Lee, Zhimin Wang, Domenico Corradi, Stefano La Rosa, Silvio Danese, Jun Yang, James F. Markmann, Gian Vincenzo Zuccotti, Reza Abdi, Franco Folli, Paolo Fiorina

Publications: Contribution to journal › Article › Peer Reviewed

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-1R^pos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA 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 of colorectal cancer.

Original language	English
Pages (from-to)	1302-1319.e12
Journal	Cell Metabolism
Volume	36
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2024.05.001
Publication status	Published - 4 Jun 2024
Externally published	Yes

Funding

We thank Dr. Thorens for providing us with the anti-GLP-1R antibody used for pathology studies. We thank \u201C Fondazione Romeo and Enrica Invernizzi \u201D for their extraordinary support. F.D. was supported by the Italian Ministry of Health grant RF-2021-12372897 and by the Italian Ministry of University and Research grant 2022JY9CP . R.A. is supported by the NIH grant K24 AI116925 . P.F., C.L., and M.B.N. are supported by the Italian Ministry of University Research grants 20229ZA2YF , 2022NH9MXB , and 20225HWJMB , respectively.

Austrian Fields of Science 2012

302012 Diabetology

Keywords

alloimmunity
cancer
GLP-1R
GLP-1R agonists
GLP-1R signaling
immune checkpoint

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cmet.2024.05.001

Cite this

Ben Nasr, M., Usuelli, V., Dellepiane, S., Seelam, A. J., Fiorentino, T. V., D'Addio, F., Fiorina, E., Xu, C., Xie, Y., Balasubramanian, H. B., Castillo-Leon, E., Loreggian, L., Maestroni, A., Assi, E., Loretelli, C., Abdelsalam, A., El Essawy, B., Uccella, S., Pastore, I., ... Fiorina, P. (2024). Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule. Cell Metabolism, 36(6), 1302-1319.e12. https://doi.org/10.1016/j.cmet.2024.05.001

@article{1df790eeb2ae4dc3b62982fabf79caf1,

title = "Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule",

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.",

keywords = "alloimmunity, cancer, GLP-1R, GLP-1R agonists, GLP-1R signaling, immune checkpoint",

author = "\{Ben Nasr\}, Moufida and Vera Usuelli and Sergio Dellepiane and Seelam, \{Andy Joe\} and Fiorentino, \{Teresa Vanessa\} and Francesca D'Addio and Emma Fiorina and Cong Xu and Yanan Xie and Balasubramanian, \{Hari Baskar\} and Eduardo Castillo-Leon and Lara Loreggian and Anna Maestroni and Emma Assi and Cristian Loretelli and Ahmed Abdelsalam and \{El Essawy\}, Basset and Silvia Uccella and Ida Pastore and Lunati, \{Maria Elena\} and Gianmarco Sabiu and Adriana Petrazzuolo and Giacomo Ducci and Elena Sacco and Lucia Centofanti and Massimo Venturini and Serena Mazzucchelli and Deborah Mattinzoli and Masami Ikehata and Giuseppe Castellano and Gary Visner and Liu Kaifeng and Lee, \{Kang Mi\} and Zhimin Wang and Domenico Corradi and \{La Rosa\}, Stefano and Silvio Danese and Jun Yang and Markmann, \{James F.\} and Zuccotti, \{Gian Vincenzo\} and Reza Abdi and Franco Folli and Paolo Fiorina",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = jun,

day = "4",

doi = "10.1016/j.cmet.2024.05.001",

language = "English",

volume = "36",

pages = "1302--1319.e12",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Elsevier",

number = "6",

}

Ben Nasr, M, Usuelli, V, Dellepiane, S, Seelam, AJ, Fiorentino, TV, D'Addio, F, Fiorina, E, Xu, C, Xie, Y, Balasubramanian, HB, Castillo-Leon, E, Loreggian, L, Maestroni, A, Assi, E, Loretelli, C, Abdelsalam, A, El Essawy, B, Uccella, S, Pastore, I, Lunati, ME, Sabiu, G, Petrazzuolo, A, Ducci, G, Sacco, E, Centofanti, L, Venturini, M, Mazzucchelli, S, Mattinzoli, D, Ikehata, M, Castellano, G, Visner, G, Kaifeng, L, Lee, KM, Wang, Z, Corradi, D, La Rosa, S, Danese, S, Yang, J, Markmann, JF, Zuccotti, GV, Abdi, R, Folli, F & Fiorina, P 2024, 'Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule', Cell Metabolism, vol. 36, no. 6, pp. 1302-1319.e12. https://doi.org/10.1016/j.cmet.2024.05.001

TY - JOUR

T1 - Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule

AU - Ben Nasr, Moufida

AU - Usuelli, Vera

AU - Dellepiane, Sergio

AU - Seelam, Andy Joe

AU - Fiorentino, Teresa Vanessa

AU - D'Addio, Francesca

AU - Fiorina, Emma

AU - Xu, Cong

AU - Xie, Yanan

AU - Balasubramanian, Hari Baskar

AU - Castillo-Leon, Eduardo

AU - Loreggian, Lara

AU - Maestroni, Anna

AU - Assi, Emma

AU - Loretelli, Cristian

AU - Abdelsalam, Ahmed

AU - El Essawy, Basset

AU - Uccella, Silvia

AU - Pastore, Ida

AU - Lunati, Maria Elena

AU - Sabiu, Gianmarco

AU - Petrazzuolo, Adriana

AU - Ducci, Giacomo

AU - Sacco, Elena

AU - Centofanti, Lucia

AU - Venturini, Massimo

AU - Mazzucchelli, Serena

AU - Mattinzoli, Deborah

AU - Ikehata, Masami

AU - Castellano, Giuseppe

AU - Visner, Gary

AU - Kaifeng, Liu

AU - Lee, Kang Mi

AU - Wang, Zhimin

AU - Corradi, Domenico

AU - La Rosa, Stefano

AU - Danese, Silvio

AU - Yang, Jun

AU - Markmann, James F.

AU - Zuccotti, Gian Vincenzo

AU - Abdi, Reza

AU - Folli, Franco

AU - Fiorina, Paolo

PY - 2024/6/4

Y1 - 2024/6/4

N2 - 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.

AB - 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.

KW - alloimmunity

KW - cancer

KW - GLP-1R

KW - GLP-1R agonists

KW - GLP-1R signaling

KW - immune checkpoint

UR - https://www.scopus.com/pages/publications/85194396750

U2 - 10.1016/j.cmet.2024.05.001

DO - 10.1016/j.cmet.2024.05.001

M3 - Article

C2 - 38838642

AN - SCOPUS:85194396750

SN - 1550-4131

VL - 36

SP - 1302-1319.e12

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

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

Abstract

Funding

Austrian Fields of Science 2012

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this