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  • Title: Type I Interferon-Activated STAT4 Regulation of Follicular Helper T Cell-Dependent Cytokine and Immunoglobulin Production in Lupus.
    Author: Dong X, Antao OQ, Song W, Sanchez GM, Zembrzuski K, Koumpouras F, Lemenze A, Craft J, Weinstein JS.
    Journal: Arthritis Rheumatol; 2021 Mar; 73(3):478-489. PubMed ID: 33512094.
    Abstract:
    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.
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