Dataset Information

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

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.

SUBMITTER: Dong X

PROVIDER: S-EPMC7914134 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Dong Xuemei X Antao Olivia Q OQ Song Wenzhi W Sanchez Gina M GM Zembrzuski Krzysztof K Koumpouras Fotios F Lemenze Alexander A Craft Joe J Weinstein Jason S JS

Arthritis & rheumatology (Hoboken, N.J.) 20210129 3

<h4>Objective</h4>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.<h4>Methods</h4>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- ...[more]

PMID: 33512094

Similar Datasets

Project description:To assess circulating follicular helper T (Tfh)-like CD4+ T cells in patients with systemic lupus erythematosus (SLE) and determine their relationship to disease activity.Blood samples from patients with SLE, as well as blood samples from patients with Behçet's disease (BD) and healthy individuals as controls, were analyzed. In all samples, circulating Tfh-like cells were enumerated by flow cytometry, using, as markers, expression of CXCR5, inducible T cell costimulator (ICOS), and programmed death 1 (PD-1) protein, as well as secretion of interleukin-21 (IL-21). The frequency of circulating Tfh-like cells was compared to that of circulating plasmablasts (CD19+IgD-CD38+). In addition, the possible association of circulating Tfh-like cells with the SLE Disease Activity Index (SLEDAI) was evaluated.The subset of circulating Tfh-like T cells, identified as CXCR5(high) ICOS(high) PD-1(high) , was expanded in the blood of SLE patients compared to controls. Circulating Tfh-like cells were found to produce IL-21 and had lower expression of CCR7 as compared to that in circulating CXCR5(high) central memory T cells, thereby enabling their distinction. Expression of PD-1, but not ICOS or CXCR5, was significantly elevated in circulating Tfh-like cells from SLE patients compared to controls. PD-1 expression among CXCR5(high) circulating Tfh-like cells correlated with the SLEDAI, frequency of circulating plasmablasts, and anti-double-stranded DNA antibody positivity, but not with disease duration or past organ injury; rather, this cell profile appeared to be a reflection of current active disease.Circulating Tfh-like cells are associated with disease activity in SLE, suggesting that their presence indicates abnormal homeostasis of T cell-B cell collaboration, with a causal relationship that is central to disease pathogenesis. These findings also suggest that circulating Tfh-like cells provide a surrogate for aberrant germinal center activity in SLE, and that their PD-1 expression offers a tool for measuring disease activity and monitoring the response to therapies.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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