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 {gamma}{delta} T cells and restricts the cellularity of ROR{gamma}t+V{gamma}6+ {gamma}{delta}T cells that produce high levels of IL-17A, while promoting the expansion of V{gamma}1+ and V{gamma}4+ {gamma}{delta}T cells. Absence of GFI1 results in a pronounced bias toward the production of {gamma}{delta}T17 cells, commencing post-birth. Additionally, we observe an expansion of ROR{gamma}t+/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 {gamma}{delta}T17 cell-specific transcriptomic profile. Specifically, DN1, DN3, and {gamma}{delta} T cells lacking GFI1 show upregulation of the B-ZIP transcription factor MAF, which regulates genes critical for {gamma}{delta}T 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 V{gamma}6+ {gamma}{delta}T17 precursor cells restricting their peripheral expansion by acting upstream of a MAF dependent regulatory network. Highlights- GFI1 controls the expansion of {gamma}{delta} T cells in peripheral lymphoid organs and in barrier tissues. - GFI1 specifically restricts expansion of {gamma}{delta} 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 {gamma}{delta}T cells through the repression of Maf. - GFI1 controls a MAF+/ROR{gamma}t+ {gamma}{delta}T cell precursor cell population within the DN1e cell subset.