Restriction of IL-22-producing T cell responses and differential regulation of regulatory T cell compartments by zinc finger transcription factor Ikaros
| Autor: | Heller, Jennifer J, Schjerven, Hilde, Li, Shiyang, Lee, Aileen, Qiu, Ju, Chen, Zong-Ming E, Smale, Stephen T, Zhou, Liang |
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| Rok vydání: | 2014 |
| Předmět: |
STAT3 Transcription Factor
Nuclear Receptor Subfamily 1 Member 3 Knockout T-Lymphocytes Immunology Inbred C57BL Autoimmune Disease Mice Ikaros Transcription Factor Transforming Growth Factor beta Group F Receptors Genetics Animals 2.1 Biological and endogenous factors Aetiology Mucosal Interleukins Inflammatory and immune system Interleukin-17 Enterobacteriaceae Infections Immunity Forkhead Transcription Factors Regulatory Infectious Diseases Aryl Hydrocarbon Mutation Citrobacter rodentium Th17 Cells Infection |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950), vol 193, iss 8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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