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Graft-versus-host disease: establishing IL-33 as an important costimulatory molecule
James Ferrara, Mariano Prado-Acosta
James Ferrara, Mariano Prado-Acosta
Published June 15, 2022
Citation Information: J Clin Invest. 2022;132(12):e160692. https://doi.org/10.1172/JCI160692.
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Commentary

Graft-versus-host disease: establishing IL-33 as an important costimulatory molecule

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Abstract

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.

Authors

James Ferrara, Mariano Prado-Acosta

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Figure 1

IL-33 promotes Th1 differentiation in GVHD.

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IL-33 promotes Th1 differentiation in GVHD.
The alloHCT conditioning reg...
The alloHCT conditioning regimen damages the GI epithelium and FRCs that in turn produce IL-33, which binds to ST2 on donor Th1 cells. TCR recognition of allogeneic major histocompatibility complex (MHC) promotes Th1 cell differentiation and expansion, promoting GVHD and further epithelial damage.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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