The Kidney–Immune Axis: How Erythropoietin Regulates Tolerance and Rejection

Erythropoietin (EPO) is classically viewed as a kidney-derived hormone essential for erythropoiesis, yet accumulating evidence places it at the center of complex interactions between the kidney and the immune system. The kidney is both a frequent target of immune-mediated injury and an organ with distinctive tolerogenic properties, capable in experimental models of inducing acceptance of otherwise rejection-prone allografts. Herein, we review experimental and clinical data showing that EPO, through its homodimeric EPO receptor (EPOR) or heterodimer EPOR/CD131 receptors, shapes both adaptive and innate immunity in ways that are directly relevant to tolerance and rejection. EPO selectively restrains effector T cells while preserving and expanding regulatory T cells through a macrophage-mediated production of active transforming growth factor β. EPO inhibits T_H17 differentiation and skews the T follicular helper/T follicular regulatory (T_FH/T_FR) balance toward regulation, resulting in reduced germinal center B-cell activity and diminished allo- and autoantibody production. In macrophages, EPO signaling limits proinflammatory cytokine production, promotes an M2-like phenotype, enhances clearance of apoptotic cells, and counteracts trained immunity programs that otherwise accelerate allograft rejection. Studies in posttransplant erythrocytosis and lupus models support a nonredundant role for endogenous EPO as a physiological mechanism of peripheral immune tolerance. Similarly, the activation of the EPO–EPOR axis in tumor-associated macrophages drives immune suppression and resistance to immune checkpoint inhibitors. Integrating these insights, we propose that EPO functions as a key rheostat of renal and systemic immunity, and discuss how harnessing this pathway may offer novel strategies to promote transplant tolerance while minimizing oncologic risk.