GATA3 expressing CD4 T cells promote intestinal graft-versus-host disease 2306818

Abstract

Abstract Introduction Hematopoietic cell transplantation (HCT) is a curative therapy for blood cancers but is complicated by graft-versus-host disease (GVHD), where donor CD4+ T helper (Th) cells drive gut pathology. Defining factors that drive pathogenic Th cell differentiation in the gut promises to inform therapies that mitigate GVHD without impacting the beneficial anti-cancer activity of HCT therapy. In our work, we identified GATA3 as a key transcription factor that may facilitate the development of gut pathogenic Th cells after HCT. We hypothesized that Th cell deletion of GATA3 will impair pathogenic Th cell differentiation and improve clinical outcomes in a murine GVHD model. Methods Using a murine allo-HCT model, we transplanted T cell-depleted bone marrow from WT C57BL/6 donors and splenocytes from C57BL/6-Gata3fl/fl Rosa26ERT2-Cre donors into irradiated BALB/c recipients. Donor cell GATA3 deletion was induced via tamoxifen treatment of recipient mice. Disease severity, intestinal pathology, donor cell trafficking, cytokine/granzyme expression, and innate immune infiltration were assessed by clinical scoring, histology, flow cytometry, and ex vivo Th cell stimulation. Results GATA3 deletion reduced intestinal GVHD pathology and impaired early donor T cell trafficking and persistence in the gut. While IFN-γ and IL-17A production were largely unaffected in early timepoints, GATA3 was required for heightened granzyme A expression, sustained GM-CSF production and chronic GM-CSF-driven intestinal eosinophilia at later timepoints. Analysis of human GVHD samples exhibited enrichment of eosinophil chemotactic pathways, mirroring murine findings. Conclusion GATA3 promotes intestinal GVHD by supporting donor T cell gut infiltration, granzyme A expression, and sustained GM-CSF-dependent eosinophilia. These findings identify GATA3 as a key regulator of pathogenic Th responses and a potential therapeutic target for mitigating intestinal GVHD. Funding Source Purdue Institute for Cancer Research Topic Categories Transplantation Immunology (TRAN)