The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

Dawn K. Reichenbach, Vincent Schwarze, Benjamin M. Matta, Victor Tkachev, Elisabeth Lieberknecht, Quan Liu, Brent H. Koehn, Dietmar Pfeifer, Patricia A. Taylor, Gabriele Prinz, Heide Dierbach, Natalie Stickel, Yvonne Beck, Max Warncke, Tobias Junt, Annette Schmitt-Graeff, Susumu Nakae, Marie Follo, Tobias Wertheimer, Lukas SchwabJason Devlin, Simon C. Watkins, Justus Duyster, James L.M. Ferrara, Heth R. Turnquist, Robert Zeiser, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-a production was significantly reduced in il33-/- recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2-/- vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2-/- T cells, and linked to reduced interferon-g production by st2-/- vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic celltransplantation byexogenousST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy.

Original languageEnglish
Pages (from-to)3183-3192
Number of pages10
JournalBlood
Volume125
Issue number20
DOIs
StatePublished - 2015
Externally publishedYes

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