title: 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.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Department of Microbiology, and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Heller
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095; Department of Laboratory Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA 94143; and Hilde.Schjerven@ucsf.edu l-zhou@northwestern.edu.
authors.forename: Hilde
authors.initials: H
authors.lastname: Schjerven
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Department of Microbiology, and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Shiyang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Department of Microbiology, and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Aileen
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Department of Microbiology, and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Ju
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822.
authors.forename: Zong-Ming E
authors.initials: ZM
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Department of Microbiology, and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Hilde.Schjerven@ucsf.edu l-zhou@northwestern.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018928:Immunity, Mucosal; D020381:Interleukin-17 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D000097043:Interleukin-22; D000098546:Interleukin-21
chemical_list: D051858:Forkhead Transcription Factors; D051740:Ikaros Transcription Factor; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D000097043:Interleukin-22; D000098546:Interleukin-21; C498833:Foxp3 protein, mouse; C494087:Stat3 protein, mouse; C497238:Zfpn1a1 protein, mouse