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

Abstract GFI1 is a DNA-binding zinc finger transcription factor regulating 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+ γδT cells that produce high levels of IL-17A, while promoting the expansion of Vγ1+ and Vγ4+ γδT cells. Absence of GFI1 results in a pronounced bias toward the production of γδT17 cells, commencing post-birth. 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 knock-out (KO) 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 γδT cells, such as Il17a, Il22, and Blk that are all induced in Gfi1 deficient cells. 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. Highlights - GFI1 controls the expansion of γδ T cells in peripheral lymphoid organs and in barrier tissues. - GFI1 specifically restricts expansion of γδ T cells secreting IL-17 by acting upstream of a MAF dependent transcriptional regulatory network. - GFI1 plays a cell intrinsic role in controlling the generation of γδT cells through the repression of Maf. - GFI1 controls a MAF+/RORγt+ γδT cell precursor cell population within the DN1e cell subset. Competing Interest Statement The authors have declared no competing interest. Footnotes Section referring to Fig 4 updated, Figs and suppl. Figs. updated, new Fig. 2A