Diverse Il-6 Signalling Modalities Drive Pathogenic T Cell Differentiation And Graft-Versus-Host-Disease After Allotransplantation

Abstract Allogeneic stem cell transplantation (alloSCT) and graft-versus-host disease (GVHD) are characterized by systemic interleukin 6 (IL-6) dysregulation, which plays a significant role in shaping donor immune responses and T cell polarization. GVHD is a T cell-mediated disease and the severity and tissue distribution is heavily influenced by T cell-derived cytokines, therefore it is critical to understand the factors that drive T cell polarization in this context to inform therapeutic strategies. IL-6 has a unique receptor system composed of IL-6Ra and the signal transducing molecule gp130, in which signaling occurs via multiple pathways either directly (classical), indirectly via a soluble IL-6 receptor (trans), or presented via antigen presenting cells (cluster). We examined the influence of IL-6 signaling modalities on T cell polarization following allotransplantation, where we found specific targeting of these pathways modulates GVHD outcomes. Using donor grafts composed of IL-6Ra deficient T cells resulted in a profound loss of pathogenic Th17/Th22 differentiation and increased GVHD survival, demonstrating these populations are highly dependent upon classical IL-6 signaling post-transplant. Whilst targeting cluster signaling through IL-6Ra deficient DC had no effect on T cell cytokine responses, trans-signaling inhibition via soluble gp130-Fc resulted in severe skin GVHD. This effect was due to significant expansion of pathogenic donor Th22 and was prevented by donor IL-22 deficiency. These data demonstrate an important role for IL-6 trans signaling in regulating pathogenic T cell polarization pathways following allotransplantation and support IL-6 classical signaling as an important target for GVHD prevention.