J Immunol. 2026 Jul 10;215(7):vkag190. doi: 10.1093/jimmun/vkag190.
ABSTRACT
Hematopoietic cell transplantation (HCT) is a curative immunotherapy for hematologic malignancies such as acute myeloid leukemia, primarily through graft-versus-tumor (GVT) effects mediated by donor T cells. However, up to 60% of recipients develop graft-versus-host disease (GVHD), with intestinal involvement being a major contributor to morbidity and mortality. While CD8 T cells drive GVT, CD4 T helper (Th) cells are largely the key mediators of intestinal GVHD. Although IFN-γ-producing Th1 cells have been implicated in this process, recent evidence suggests a more complex role for Th cell subtypes. In our study, we identify the transcription factor GATA3, often associated with Th2 function, as a key regulator of Th cell proliferation, gut persistence, and cytokine production. Specifically, donor cell GATA3 was required for the early production of gut‑damaging granzyme A by intestinal Th cells and sustained granulocyte-macrophage colony-stimulating factor (GM‑CSF) production at later phases of the intestinal GVHD response. GATA3‑mediated maintenance of GM‑CSF expression during these later stages of disease was associated with increased intestinal eosinophil recruitment and activation, features that have been linked to GVHD severity in humans. Collectively, our findings demonstrate that GATA3‑expressing Th cells contribute to intestinal GVHD pathogenesis by sustaining GM-CSF-driven inflammatory circuits and promoting chronic eosinophilia. Targeting GATA3, or its downstream effector pathways, may therefore represent a novel therapeutic strategy to attenuate intestinal GVHD while preserving the overall efficacy of HCT.
PMID:42498264 | DOI:10.1093/jimmun/vkag190