Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells

Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):9394-9. doi: 10.1073/pnas.1511711112. Epub 2015 Jul 13.


IL-21 is a type I cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4(+) T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4(+) T cells. RNA-Seq analysis of CD4(+) T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γ expression in CD4(+) T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4(+) T cells from patients with autosomal dominant hyper-IgE syndrome, which is caused by STAT3 deficiency, as well as in cells from STAT1 gain-of-function patients. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.

Keywords: AD-HIES; IFN-γ; IL-21; STATs; T cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Cytokines / immunology
  • Flow Cytometry
  • Gene Expression Regulation
  • Immunoglobulin E / immunology
  • Interferon-gamma / immunology
  • Interleukins / immunology*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Phosphorylation
  • STAT1 Transcription Factor / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction
  • T-Box Domain Proteins / metabolism


  • Cytokines
  • Interleukins
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Immunoglobulin E
  • Interferon-gamma
  • interleukin-21

Associated data

  • GEO/GSE63204