Approximately half of patients with hematologic malignancy who are treated with allogeneic hematopoietic stem cell transplantation (alloHCT) experience graft-versus-host disease (GVHD), which has high mortality rates despite immunosuppressive therapy. IL-12 is known to drive donor T cells toward an inflammatory Th1 lineage in GVHD, but other mechanisms also promote pathological Th1 alloimmune responses. In this issue of the
JCI
, Dwyer et al. report on their use of transgenic mice and alloHCT models of GVHD to demonstrate that IL-33 acts directly on donor T cells to increase Tbet expression independently of IL-12. Notably, IL-33 amplified T cell receptor–signaling pathways and inhibited production of regulatory molecules. These findings firmly establish IL-33 as an important costimulatory molecule for Th1 cells during GVHD and provide a target for reducing GVHD, especially in the gastrointestinal (GI) tract, where damage drives mortality.
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