TY - JOUR
T1 - Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival
AU - Purroy, Carolina
AU - Fairchild, Robert L.
AU - Tanaka, Toshiaki
AU - Baldwin, William M.
AU - Manrique, Joaquin
AU - Madsen, Joren C.
AU - Colvin, Robert B.
AU - Alessandrini, Alessandro
AU - Blazar, Bruce R.
AU - Fribourg, Miguel
AU - Donadei, Chiara
AU - Maggiore, Umberto
AU - Heeger, Peter S.
AU - Cravedi, Paolo
N1 - Publisher Copyright:
Copyright © 2017 by the American Society of Nephrology.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2016101100
DO - 10.1681/ASN.2016101100
M3 - Article
C2 - 28302753
AN - SCOPUS:85020557457
SN - 1046-6673
VL - 28
SP - 2377
EP - 2392
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 8
ER -