GFI1 as a novel regulator of γδ T cell development and the IL-17/IFN-γ lineage commitment

GFI1 is a DNA-binding transcription factor that regulates the commitment of hematopoietic precursors to myeloid and lymphoid lineages. Here we report that GFI1 is expressed in γδ T cells and restricts the cellularity of RORγt⁺Vγ6⁺ γδ T cells that produce high levels of IL-17A while promoting the expansion of Vγ1⁺ and Vγ4⁺ γδ T cells. GFI1 deficiency results in an expansion of Vγ6⁺ γδT17 cells that starts post-birth and is strongly exacerbated upon challenge with an inflammatory allergen. Additionally, we observe an expansion of RORγt⁺/MAF⁺ cells within the thymic DN1e population of GFI1-deficient mice. The DN1e population, along with other DN subsets in GFI1-deficient mice, exhibits a distinctive γδT17 cell-specific transcriptomic profile. Specifically, DN1, DN3, and γδ T cells lacking GFI1 show upregulation of the B-ZIP transcription factor MAF, which regulates genes critical for γδ T cells, such as IL-17a, IL-22, and Blk. The Maf gene is occupied by GFI1 in DN pre-T cells at cognate binding sites in its promoter region, suggesting that GFI1 acts as a direct repressor of Maf. We conclude that GFI1 functions as a novel regulator of Vγ6⁺ γδT17 precursor cells restricting their peripheral expansion by acting upstream of a MAF-dependent regulatory network.