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While strategies to mitigate GF have been explored, such as intensified conditioning or donor T cell supplementation, these approaches carry significant risks, including increased toxicity and graft-versus-host disease (GVHD). Recent studies have highlighted the glucagon-like peptide-1 receptor (GLP1R) as a critical regulator of immune homeostasis, yet its role in HSC engraftment remains unexplored. Here, we demonstrated that GLP1R deficiency in recipient mice leads to a profound increase in GF following MHC-mismatched allogeneic HSCT. Although GLP1R knockout (GLP1RKO) and wild-type (WT) mice exhibited comparable survival and engraftment following syngeneic or minor antigen-mismatched transplants, GLP1RKO mice undergoing MHC-mismatched HSCT experienced significantly greater weight loss, earlier mortality, and reduced donor chimerism. Histologic and cytokine analyses confirmed that this phenotype is not driven by GVHD, but rather by early graft rejection. Depletion of CD90+ recipient T cells prior to transplantation rescued engraftment in GLP1RKO mice, further supporting a model in which GLP1R signaling restrains host lymphocyte-mediated graft rejection. These findings identify GLP1R as a novel regulator of allogeneic HSC engraftment and suggest that GLP1R agonists, widely used for metabolic disorders, may have therapeutic potential in preventing HSC graft rejection. Given the lack of targeted interventions for HSC graft rejection, further studies are warranted to investigate GLP1R-directed therapies in the context of allogeneic HSCT.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf251","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T10:34:16Z","timestamp":1758710056000},"source":"Crossref","is-referenced-by-count":1,"title":["Glucagon-like peptide-1 receptor signaling deficiency exacerbates hematopoietic stem cell graft rejection in mice"],"prefix":"10.1093","volume":"215","author":[{"given":"Mark","family":"Rusznak","sequence":"first","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United 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Y","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uttam","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Hematology Oncology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masako","family":"Abney","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianni","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Hematology Oncology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M","family":"Warren","sequence":"additional","affiliation":[{"name":"United States Department of Veterans Affairs, Tennessee Valley Healthcare System , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J","family":"Drucker","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto , Toronto, ON,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D","family":"Niswender","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Division of Hematology Oncology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Kon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]},{"name":"Division of Hematology Oncology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine N","family":"Gibson-Corley","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine N","family":"Cahill","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth R","family":"Cooke","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University, School of Medicine , Baltimore, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"R 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