title: Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival.
abstract: Although spontaneous kidney transplant acceptance/tolerance occurs in mice and occasionally in humans, mechanisms remain unclear. Herein we test the hypothesis that EPO, a hormone predominantly produced by the adult kidney, has immunomodulating properties that are required for spontaneous kidney graft acceptance.In vitro, in a manner dependent on the EPO receptor and CD131 on antigen-presenting cells, EPO induced the secretion of active TGFβby antigen-presenting cells, which in turn converted naïve CD4+T cells into functional Foxp3+regulatory T cells (Treg). In murine transplant models, pharmacologic downregulation of kidney-derived EPO prevented spontaneous Treg generation. In a controlled, prospective cohort clinical study, EPO administration at doses used to correct anemia augmented the frequency of peripheral CD4+CD25+CD127loT cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferationin vitro viatyrosine phosphatase SHP-1-dependent uncoupling of IL-2Rβsignaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2Rγsignaling and maintaining constitutively quenched IL-2Rβsignaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGFβmRNA and abrogated kidney allograft acceptance. Together, our findings delineate the protolerogenic properties of EPO in inhibiting conventional T cells while simultaneously promoting Treg induction, and suggest that manipulating the EPO/EPO receptor signaling axis could be exploited to prevent and/or treat T cell-mediated pathologies, including transplant rejection.
authors.affiliation: Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute and.|Nephrology Service, Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Purroy
authors.affiliation: Department of Immunology, The Cleveland Clinic, Cleveland, Ohio.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
authors.affiliation: Department of Immunology, The Cleveland Clinic, Cleveland, Ohio.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Immunology, The Cleveland Clinic, Cleveland, Ohio.
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.affiliation: Nephrology Service, Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Manrique
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Colvin
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Alessandrini
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fribourg
authors.affiliation: Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadei
authors.affiliation: Kidney and Pancreas Transplantation Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Maggiore
authors.affiliation: Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute and.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
authors.affiliation: Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute and paolo.cravedi@mssm.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cravedi
mesh_terms: D000818:Animals; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation; D051379:Mice; D011446:Prospective Studies; D020239:Receptor Cross-Talk; D017467:Receptors, Erythropoietin / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D017467:Receptors, Erythropoietin
keywords: Regulatory T cell; acute allograft rejection; erythropoietin; transplantation