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

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 effectsonantibodyproduction 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, murinemodels of organ transplantation and lupus nephritis, andmice conditionally deficient for the EPOR expressed on T cells or B cells. Results Inwild-typemice, recombinantEPOinhibited primary, T cell-dependent humoral immunity tomodel 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 showedthat EPOdirectly prevented T-FH differentiation and function via a STAT5-dependentmechanismthat 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.

Automated summary

The study found that EPO can inhibit T-FH-dependent antibody formation by reducing the frequency and function of T-FH cells. This has potential implications for treating antibody-mediated diseases, including kidney diseases.