IL-39/IL-39R Signaling Drives Acute Graft-versus-Host Disease by Promoting Pathogenic T-Cell Responses 2259690

Abstract Introduction Acute graft-versus-host disease (aGVHD) remains a life-threatening complication of allogeneic hematopoietic cell transplantation. Among IL-12 family cytokines, the newly identified IL-39, composed of IL-23p19 and EBI3, ligands IL-39 receptor, a complex of IL-23Rα and gp130. IL-39 has been implicated in inflammatory disorders, but its contribution to aGVHD and graft-versus-leukemia (GVL) remains undefined. Methods Murine and human T cells were stimulated with allogeneic APCs in the presence of recombinant human IL-39 (rhIL-39) to test the effect of IL-39 in T-cell response in vitro. Proximity ligation assay (PLA) was used to detect IL-23Rα/GP130 heterodimerization. T-cell pathogenicity in GVHD was measured in murine allogeneic bone marrow transplantion (BMT). The GVL activity was assessed using MLL-AF9 leukemia challenge. A xenogeneic GVHD (xeno-GVHD) model with human PBMCs was used to evaluate IL-39’s effect on human T-celll responses. Results rhIL-39 enhanced proliferation and production of IFN-γ, TNF-α, and GM-CSF, promoted Th1/Th17 polarization, and suppressed Foxp3+Treg differentiation in murine and human T cells. It induced robust STAT1/3 phosphorylation in IL-23Rαhigh Th17 cells and PLA assay confirmed IL-23Rα/gp130 heterodimerization. In murine BMT models, recipients receiving IL-23Rα-/- or DKO donor cells exhibited less GVHD compared to those of WT or IL-12Rβ1-/- cells while preserving GVL activity. rhIL-39 markedly increased GVHD scores, decreased survival, and expanded IFN-γ+, TNF-α+, and IL-17+CD4+ T cells while reducing Foxp3+ Tregs in the recipients of WT but not IL-23Rα-/- T cells. In the xeno-GVHD model, rhIL-39 aggravated GVHD with reduced survival and elevated human T-cell infiltration and inflammatory cytokines. Taken together, IL-39 enhances T-cell pathogenicity in GVHD through IL-23Rα. Conclusion IL-39/IL-39R signaling drives aGVHD pathogenesis and represents a promising therapeutic target for aGVHD while preserving GVL responses. Funding Source NIH, Advancing A Healthier Wisconsin Endowment Topic Categories Transplantation Immunology (TRAN)