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 a manner dependent on the EPO receptor and CD131 on antigen-presenting cells, EPO induced the secretion of active TGF by 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 CD4CD25CD127 T cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferation tyrosine phosphatase SHP-1-dependent uncoupling of IL-2R signaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2R signaling and maintaining constitutively quenched IL-2R signaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGF 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.

Large-Scale Generation of Human Allospecific Induced Tregs With Functional Stability for Use in Immunotherapy in Transplantation

“…In addition, immunomodulatory agents for in vivo iTreg generation can be considered such as hormone erythropoietin, as its application to patients with chronic kidney disease resulted in an increase of Tregs after 6 months of treatment. In this context, in vitro assays confirmed that erythropoietin has an effect on APCs inducing the production of TGF-β1, an important cytokine for iTreg generation (46).…”

Erythropoietin and its derivatives: from tissue protection to immune regulation

“…Very recently, a series of studies revealed that EPO had an immunoregulatory effect by acting on T cells [49][50][51] . EPO directly inhibited the proliferation of conventional T cells (Tconvs) in a dose-dependent manner without inducing apoptosis and conversely facilitated Treg proliferation 49,50 . The mechanism lay in the crosstalk between EPO signaling and the proliferative signaling of T cells.…”

Regulatory T Cells and Kidney Transplantation

“…Metformin promotes phosphorylation of p-STAT5 and FOXP3 (27). Erythropoietin, on the other hand, is reported to inhibit proliferation of conventional T cells, while simultaneously sparing Treg proliferation (28). Finally, the use of low-dose recombinant IL-2 has been considered as a potential means of expanding Tregs (29), although it appears to have a narrow therapeutic window because of the risk of stimulating natural killer cell activity (30).…”