TGF-β is a common factor important for the differentiation of pro-inflammatory Th17 and anti-inflammatory inducible Treg cells. However, the precise molecular mechanisms underlying the fate decision of differentiating CD4+ T cells in the presence of TGF-β is poorly understood. Here, we show that distinctive N-terminal DNA-binding zinc fingers of Ikaros play essential roles in Treg and Th17 fate decision. Ikaros has a highly conserved DNA-binding domain near the N-terminus with four tandem zinc fingers. Zinc fingers 2 and 3 are required for stable binding to DNA, whereas fingers 1 and 4 appear to be important for differentially modulating binding properties to specific sites at target genes. Our data show that T cells lacking Ikaros zinc finger 4 but not 1 failed to differentiate into Foxp3+ Tregs upon TGF-β stimulation. Instead, TGF-β-skewed Ikaros zinc finger 4 mutant cells displayed aberrant upregulation of Th17-associated cytokines IL-17 and IL-22. IL-17 but not IL-22 upregulation is dependent on transcription factor RORγt. Aryl hydrocarbon receptor, an essential transcription factor required for IL-22 expression, was unexpectedly decreased. Together, our data uncover a novel selective requirement for Ikaros zinc fingers in the differentiation of Treg and Th17 cells and an intricate interplay among various transcription factors in programming Th17/Treg lineages. We are currently examining the role of Ikaros zinc finger 4 in infection and autoimmunity.
- Copyright © 2013 by The American Association of Immunologists, Inc.