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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.

Erythropoietin Reduces Auto- and Alloantibodies by Inhibiting T Follicular Helper Cell Differentiation