Type I Interferon–Activated STAT4 Regulation of Follicular Helper T Cell–Dependent Cytokine and Immunoglobulin Production in Lupus
| Autor: | Gina M. Sanchez, Joe Craft, Alexander Lemenze, Jason S. Weinstein, Krzysztof Zembrzuski, Wenzhi Song, Fotios Koumpouras, Olivia Q. Antao, Xuemei Dong |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment T cell Immunology Biology medicine.disease_cause Autoimmunity 03 medical and health sciences 0302 clinical medicine Rheumatology immune system diseases Interferon medicine Immunology and Allergy skin and connective tissue diseases STAT4 B cell Lupus erythematosus Systemic lupus erythematosus medicine.disease 030104 developmental biology medicine.anatomical_structure Cytokine 030215 immunology medicine.drug |
| Zdroj: | Arthritis & Rheumatology. 73:478-489 |
| ISSN: | 2326-5205 2326-5191 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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