Signal Transducer and Activator of Transcription 3 Hyperactivation Associates With Follicular Helper T Cell Differentiation and Disease Activity in Rheumatoid Arthritis

Deng, Jun; Fan, Chaofan; Gao, Xin; Zeng, Quan; Guo, Ruru; Wei, Yunbo; Chen, Zhian; Chen, Yanan; Gong, Danni; Feng, Jia Nuo; Xia, Yan; Xiang, Shifei; Gong, Shushi; Lin, Yuan; Shen, Wei Feng; Shen, Wang; Lin, Lin; Jiang, Ting; He, Dongyi; Lu, Liangjing; Chen, Xiaoxiang; Yu, Di

doi:10.3389/fimmu.2018.01226

Cited by 37 publications

(35 citation statements)

References 48 publications

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“…In the present study, we observed significantly up-regulated expression of pSTAT3 in peripheral Tfh cells, as expected after being stimulated with IL-6, and significantly increased serum IL-6, especially in patients with active RA. Meanwhile, there was positive correlation between pSTAT3 expression and serum IL-6, which was consistent with the research of Deng et al [ 40 ]. Further analysis revealed that pSTAT3 expression was positively correlated with circulating Tfh cell frequency, but there was no correlation between pSTAT3 expression and Tfh/Tfr ratio.…”

Section: Discussionsupporting

confidence: 91%

Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis

Niu

Huang

et al. 2018

Arthritis Res Ther

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BackgroundFollicular helper T (Tfh) cells are specialized in helping B lymphocytes, which play a central role in autoimmune diseases that have a major B cell component, such as in rheumatoid arthritis (RA). Follicular regulatory T (Tfr) cells control the over-activation of Tfh and B cells in germinal centers. Dysregulation of Tfh cells and Tfr cells has been reported to be involved in the pathogenesis of some autoimmune diseases. However, the balance of Tfh and Tfr cells, and their roles in the development and progression of RA are still not clear.MethodsIn this study, we enrolled 44 patients with RA (20 patients with active RA and 24 patients with inactive RA) and 20 healthy controls, and analyzed the frequencies of circulating Tfh and Tfr cells, expression of programmed death-1 (PD-1), inducible co-stimulator (ICOS), intracellular IL-21, and pSTAT3 in Tfh cells, and serum levels of IL-6. The correlation among these parameters and that of Tfh or Tfr cells with disease activity were also analyzed.ResultsPatients with RA (especially active RA) had higher frequencies of Tfh cells, but lower percentages of Tfr cells, thereby resulting in elevated ratios of Tfh/Tfr. Expression levels of PD-1 and IL-21 in Tfh cells were higher in patients with RA than in healthy subjects, while no difference in ICOS expression was observed between patients and controls. Both pSTAT3 expression and serum IL-6 levels increased in patients with RA, and positive correlation between them was observed. Additionally, pSTAT3 expression was positively correlated with Tfh cell frequency. The Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP) was negatively correlated with Tfr cell frequency, but was positively correlated with both Tfh/Tfr ratio and PD-1 expression.ConclusionsResults demonstrated that enhanced IL-6/pSTAT3 signaling may contribute to promotion of Tfh cells, consequently skewing the ratio of Tfh to Tfr cells, which may be crucial for disease progression in RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1690-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis

Niu

Huang

et al. 2018

Arthritis Res Ther

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“…TGF-β, IL-6, and IL-6R can mediate STAT3-induced Bcl-6 expression and promote Tfh differentiation in human (Wu et al, 2015). In STAT3 deficiency, Tfh cells develop at a slower rate, inhibit IL-21, and increase expression of IFN-γ and IL-4, leading to decreased helper activity in B cells (Park et al, 2017;Deng et al, 2018). PD-1 is a co-inhibitory molecule that is highly expressed on Tfh cells, whereas PD-1 + Tfh cells play an important role in normal immune responses (Li et al, 2018;Shi et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Effect of Sishen Pill on Tfh Cells in Mice With Experimental Colitis

et al. 2020

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The T follicular helper T (Tfh) cells play a significant role in the pathogenesis of inflammatory bowel disease (IBD), which is regulated by the Bcl-6/Blimp-1 pathway. Some studies have suggested that regulating activation of the Bcl-6/Blimp-1 pathway should be an effective method to treat IBD. Sishen Pill (SSP) has been used frequently to treat chronic colitis. Its mechanism is related to the downstream proteins in the Bcl-6/Blimp-1 pathway. However, it is unknown whether SSP regulates the function and differentiation of Tfh cells to treat IBD. In the present study, chronic colitis was induced by dextran sodium sulfate and treated with SSP for 7 days. SSP effectively treated chronic colitis, regulated the balance between Tfh10, Tfh17 and T follicular regulatory cells, while SSP increased the Blimp-1 level, inhibited expressions of Bcl-6, T-cell costimulator, programmed death (PD)-1 and PD-ligand 1 on the surface of Tfh cells. SSP inhibited activation of BcL-6, phosphorylated signal transducer and activator of transcription (p-STAT)3, signal lymphocyte activation molecule (SLAM)associated protein but improved Blimp-1 and STAT3 expression in colonic tissues. The results indicated that SSP regulated the differentiation and function of Tfh cells to treat IBD, which was potentially related with inhibiting the Bcl-6/Blimp-1 pathway.

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“…STAT1 is necessary for IL-6-mediated Bcl6 induction during the early differentiation of Tfh cells [ 43 ]. STAT3 has been found to be critical for Tfh cell development in a Bcl6-dependent manner [ 23 ]. The major STAT3-stimulating cytokines include IL-6, IL-21, IL-12, IL-10, and TGF- β [ 23 , 56 , 57 ].…”

Section: Statsmentioning

confidence: 99%

“…STAT3 has been found to be critical for Tfh cell development in a Bcl6-dependent manner [ 23 ]. The major STAT3-stimulating cytokines include IL-6, IL-21, IL-12, IL-10, and TGF- β [ 23 , 56 , 57 ]. Besides, STAT3 regulates Bcl6 expression by cooperating with the Ikaros zinc finger transcription factors Aiolos and Ikaros [ 58 ].…”

Section: Statsmentioning

confidence: 99%

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

Sun

Zhang

et al. 2020

Journal of Immunology Research

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Helping B cells and antibody responses is a major function of CD4+T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4+T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.

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Signal Transducer and Activator of Transcription 3 Hyperactivation Associates With Follicular Helper T Cell Differentiation and Disease Activity in Rheumatoid Arthritis

Cited by 37 publications

References 48 publications

Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis

Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis

Regulatory Effect of Sishen Pill on Tfh Cells in Mice With Experimental Colitis

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

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