Background

Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown.

Methods

We assessed the effect and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell–dependent and T–independent antibody formation using in vitro culture systems, murine models of organ transplantation and lupus nephritis, and mice conditionally deficient for the EPOR expressed on T cells or B cells.

Results

In wild-type mice, recombinant EPO inhibited primary, T cell–dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T–independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell, but not B cell, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helper cells (T_FH). In vitro and in vivo experiments showed that EPO directly prevented T_FH differentiation and function via a STAT5-dependent mechanism that reduces CD4⁺ T cell expression of Bcl6. In lupus models, EPO reduced T_FH, GC B cells, and autoantibody production, and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. In vitro studies verified that EPO prevents differentiation of human T_FH cells.

Conclusions

Our findings newly demonstrate that EPO inhibits T_FH-dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney.