Premium
Type I Interferon–Activated STAT4 Regulation of Follicular Helper T Cell–Dependent Cytokine and Immunoglobulin Production in Lupus
Author(s) -
Dong Xuemei,
Antao Olivia Q.,
Song Wenzhi,
Sanchez Gina M.,
Zembrzuski Krzysztof,
Koumpouras Fotios,
Lemenze Alexander,
Craft Joe,
Weinstein Jason S.
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41532
Subject(s) - stat4 , immunology , cytokine , systemic lupus erythematosus , biology , medicine , signal transduction , stat , disease , microbiology and biotechnology , stat3
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.