Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival

Carolina Purroy, Robert L. Fairchild, Toshiaki Tanaka, William M. Baldwin, Joaquin Manrique, Joren C. Madsen, Robert B. Colvin, Alessandro Alessandrini, Bruce R. Blazar, Miguel Fribourg, Chiara Donadei, Umberto Maggiore, Peter S. Heeger, Paolo Cravedi

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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 TGFβ by antigen-presenting cells, which in turn converted naïve CD4+ T cells into functional Foxp3+ regulatory T cells (Treg). Inmurine 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+CD127lo T cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferation in vitro via tyrosine phosphatase SHP-1-dependent uncoupling of IL-2Rβ signaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2Rγ signaling and maintaining constitutively quenched IL-2Rβ signaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGFβ mRNA 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.

Original languageEnglish (US)
Pages (from-to)2377-2392
Number of pages16
JournalJournal of the American Society of Nephrology
Issue number8
StatePublished - Aug 2017

Bibliographical note

Publisher Copyright:
Copyright © 2017 by the American Society of Nephrology.


Dive into the research topics of 'Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival'. Together they form a unique fingerprint.

Cite this