Type I Interferon-Activated STAT4 Regulation of Follicular Helper T Cell-Dependent Cytokine and Immunoglobulin Production in Lupus

Arthritis Rheumatol. 2021 Mar;73(3):478-489. doi: 10.1002/art.41532. Epub 2021 Jan 29.


Objective: To assess the role of STAT4 activation in driving pathogenic follicular helper T (Tfh) cell secretion of the cytokines interleukin-21 (IL-21) and interferon-γ (IFNγ) in murine and human lupus.

Methods: The effect of STAT4-dependent Tfh cell signaling on cytokine production and autoreactive B cell maturation was assessed temporally during the course of lupus in a murine model, with further assessment of Tfh cell gene transcription performed using RNA-Seq technology. STAT4-dependent signaling and cytokine production were also determined in circulating Tfh-like cells in patients with systemic lupus erythematosus (SLE), as compared to cells from healthy control subjects, and correlations with disease activity were assessed in the Tfh-like cells from SLE patients.

Results: IL-21- and IFNγ-coproducing Tfh cells expanded prior to the detection of potentially pathogenic IgG2c autoantibodies in lupus-prone mice. Tfh cells transcriptionally evolved during the course of disease with acquisition of a STAT4-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon STAT4 signaling, driven by type I IFNs. Circulating Tfh-like cells from patients with SLE also secreted IL-21 and IFNγ, with STAT4 phosphorylation enhanced by IFNβ, in association with the extent of clinical disease activity.

Conclusion: We identified a role for type I IFN signaling in driving STAT4 activation and production of IL-21 and IFNγ by Tfh cells in murine and human lupus. Enhanced STAT4 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that STAT4 guides pathogenic cytokine and immunoglobulin production in SLE, demonstrating a potential therapeutic target to modulate autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibody Formation / immunology
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology*
  • B-Lymphocytes / immunology
  • Case-Control Studies
  • Cytokines / immunology*
  • Disease Models, Animal
  • Female
  • Humans
  • Immunoglobulins
  • Interferon Type I / immunology*
  • Interferon-gamma / immunology
  • Interleukins / immunology
  • Lupus Erythematosus, Systemic / immunology*
  • Male
  • Mice, Inbred MRL lpr
  • Middle Aged
  • RNA-Seq
  • STAT4 Transcription Factor / immunology*
  • T Follicular Helper Cells / immunology*


  • Autoantibodies
  • Cytokines
  • Immunoglobulins
  • Interferon Type I
  • Interleukins
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Stat4 protein, mouse
  • Interferon-gamma
  • interleukin-21