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 Foxp 3+ 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 + CD127 lo 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.

Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival / Purroy, Carolina; Fairchild, Robert L.; Tanaka, Toshiaki; Baldwin, William M.; Manrique, Joaquin; Madsen, Joren C.; Colvin, Robert B.; Alessandrini, Alessandro; Blazar, Bruce R.; Fribourg, Miguel; Donadei, Chiara; Maggiore, Umberto; Heeger, Peter S.; Cravedi, Paolo. - In: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. - ISSN 1046-6673. - 28:8(2017), pp. 2377-2392. [10.1681/ASN.2016101100]

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

Maggiore, Umberto;Cravedi, Paolo
2017-01-01

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 TGFβ by antigen-presenting cells, which in turn converted naïve CD4 + T cells into functional Foxp 3+ 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 + CD127 lo 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.
2017
Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival / Purroy, Carolina; Fairchild, Robert L.; Tanaka, Toshiaki; Baldwin, William M.; Manrique, Joaquin; Madsen, Joren C.; Colvin, Robert B.; Alessandrini, Alessandro; Blazar, Bruce R.; Fribourg, Miguel; Donadei, Chiara; Maggiore, Umberto; Heeger, Peter S.; Cravedi, Paolo. - In: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. - ISSN 1046-6673. - 28:8(2017), pp. 2377-2392. [10.1681/ASN.2016101100]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2857894
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 43
  • ???jsp.display-item.citation.isi??? 39
social impact