IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Andrew N. Wilkinson, Karshing Chang, Rachel D. Kuns, Andrea S. Henden, Simone A. Minnie, Kathleen S. Ensbey, Andrew D. Clouston, Ping Zhang, Motoko Koyama, Juan Hidalgo, Stefan Rose-John, Antiopi Varelias, Slavica Vuckovic, Kate H. Gartlan, Geoffrey R. Hill*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

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 and 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 (DCs) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling after targeted IL-6 receptor (IL-6R) deletion in T cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. After engraftment, donor DCs assume the same role, maintaining classical IL-6 signaling–dependent GVHD responses. Surprisingly, cluster signaling was not active after transplantation, whereas inhibition of trans signaling with soluble gp130Fc 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 important therapeutic targets after alloSCT.

Original languageAmerican English
Pages (from-to)2092-2106
Number of pages15
JournalBlood
Volume134
Issue number23
DOIs
Publication statusPublished - 5 Dec 2019

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