Restriction of IL-22–Producing T Cell Responses and Differential Regulation of Regulatory T Cell Compartments by Zinc Finger Transcription Factor Ikaros

Abstract

Proper immune responses are needed to control pathogen infection at mucosal surfaces. IL-22–producing CD4+ T cells play an important role in controlling bacterial infection in the gut; however, transcriptional regulation of these cells remains elusive. In this study, we show that mice with targeted deletion of the fourth DNA-binding zinc finger of the transcription factor Ikaros had increased IL-22–producing, but not IL-17–producing, CD4+ T cells in the gut. Adoptive transfer of CD4+ T cells from these Ikaros-mutant mice conferred enhanced mucosal immunity against Citrobacter rodentium infection. Despite an intact in vivo thymic-derived regulatory T cell (Treg) compartment in these Ikaros-mutant mice, TGF-β, a cytokine well known for induction of Tregs, failed to induce Foxp3 expression in Ikaros-mutant CD4+ T cells in vitro and, instead, promoted IL-22. Aberrant upregulation of IL-21 in CD4+ T cells expressing mutant Ikaros was responsible, at least in part, for the enhanced IL-22 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor, but not RORγt, was required for aberrant IL-22 expression by Ikaros-mutant CD4+ T cells, whereas forced expression of Foxp3 was sufficient to inhibit this aberrant cytokine production. Together, our data identified new functions for Ikaros in maintaining mucosal immune homeostasis by restricting IL-22 production by CD4+ T cells.