The transcriptional repressor Gfi1 is critical for the differentiation of pathogenic Th2 cells.

Pathogenic Th2 cells (Tpath2), which produce IL-5 and IL-13 in response to both antigen and IL-33 stimulation, play a central role in the pathogenesis of chronic type 2 inflammation. However, the molecular mechanisms driving their differentiation remain unclear. We herein demonstrate that growth factor independent 1 (Gfi1) is critical for the differentiation and function of Tpath2. In an OVA-induced mouse model of chronic allergic airway inflammation, Gfi1 was highly expressed in CD44-high IL-33Rα-positive CD4 T cells and regulatory T cells (Treg). T-cell-specific Gfi1 deficiency suppressed the accumulation of IL-33Rα-positive T cells, overall lung CD4 T cell infiltration, and eosinophilic airway inflammation. Mechanistically, in vitro analyses revealed that Gfi1 is essential for inducing IL-33Rα-positive Tpath2 cells, IL-7/IL-33-dependent IL-5 and IL-13 production, and histone H3K9 acetylation at the Il1rl1 and Il5 loci. These findings establish Gfi1 as a key regulator of Tpath2 cells and a potential therapeutic target for type 2 chronic allergic inflammatory diseases.