title: Stat4 is critical for the balance between Th17 cells and regulatory T cells in colitis.
abstract: Th17 play a central role in autoimmune inflammatory responses. Th1 are also necessary for autoimmune disease development. The interplay of Th1 signals and how they coordinate with Th17 during inflammatory disease pathogenesis are incompletely understood. In this study, by adding Stat4 deficiency to Stat6/T-bet double knockout, we further dissected the role of Stat4 in Th1 development and colitis induction. We showed that in the absence of the strong Th2 mediator Stat6, neither Stat4 nor T-bet is required for IFN-γ production and Th1 development. However, addition of Stat4 deficiency abolished colitis induced by Stat6/T-bet double-knockout cells, despite Th1 and Th17 responses. The failure of colitis induction by Stat4/Stat6/T-bet triple-knockout cells is largely due to elevated Foxp3(+) regulatory T cell (Treg) development. These results highlight the critical role of Stat4 Th1 signals in autoimmune responses in suppressing Foxp3(+) Treg responses and altering the balance between Th17 and Tregs to favor autoimmune disease.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jiangnan
authors.initials: J
authors.lastname: Xu
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Guixing
authors.initials: G
authors.lastname: Qiu
authors.forename: Girdhari
authors.initials: G
authors.lastname: Lal
authors.forename: Na
authors.initials: N
authors.lastname: Yin
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wu
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
authors.forename: Yaozhong
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D039521:CD11c Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma