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

OBJECTIVE:To assess the role of 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 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. duanyu18134-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 duanyu18134-dependent gene signature. Maintenance of Tfh cell cytokine synthesis was dependent upon duanyu18134 signaling, driven by type I IFNs. Circulating Tfh-like cells from patients with SLE also secreted IL-21 and IFNγ, with duanyu18134 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 duanyu18134 activation and production of IL-21 and IFNγ by Tfh cells in murine and human lupus. Enhanced duanyu18134 activation in Tfh cells may underlie pathogenic B cell responses in both murine and human lupus. These data indicate that duanyu18134 guides pathogenic cytokine and immunoglobulin production in SLE, demonstrating a potential therapeutic target to modulate autoimmunity. © 2020, American College of Rheumatology.

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