LAUSR

Graft-versus-host-disease (GVHD) after allogeneic stem cell transplantation (alloSCT) is characterized by interleukin 6 (IL-6) dysregulation. IL-6 can mediate effects via various pathways, including classical, trans and cluster signaling. Given the recent availability of agents that differentially inhibit these discrete signaling cascades, understanding the source, signaling and cellular targets of this cytokine is paramount to inform the design of clinical studies. Here we demonstrate that IL-6 secretion from recipient dendritic cells (DC) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling following targeted IL-6 receptor (IL-6R) deletion in T-cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. Following engraftment, donor DC assume the same role, maintaining classical IL-6 signaling-dependent GVHD responses. Surprisingly, cluster-signaling was not active after transplant, while inhibition of trans-signaling with sgp130Fc promoted severe, chronic cutaneous GVHD. The latter was a result of exaggerated polyfunctional Th22 cell expansion that was reversed by IL-22 deletion or IL-6R inhibition. Importantly, inhibition of IL-6 classical-signaling did not impair the graft-versus-leukemia effect. Together, these data highlight IL-6 classical-signaling and downstream Th17/Th22 differentiation as key therapeutic targets after alloSCT.