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The cytokine TGF-? co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells.

ABSTRACT: Understanding the developmental mechanisms of follicular helper T cells (TFH cells) in humans is relevant to the clinic. However, the factors that drive the differentiation of human CD4+ helper T cells into TFH cells remain largely undefined. Here we found that transforming growth factor-? (TGF-?) provided critical additional signals for the transcription factors STAT3 and STAT4 to promote initial TFH differentiation in humans. This mechanism did not appear to be shared by mouse helper T cells. Developing human TFH cells that expressed the transcriptional repressor Bcl-6 also expressed ROR?t, a transcription factor typically expressed by the TH17 subset of helper T cells. Our study documents a mechanism by which TFH cells and TH17 cells emerge together in inflammatory environments in humans, as is often observed in many human autoimmune diseases.

SUBMITTER: Schmitt N

PROVIDER: S-EPMC4183221 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells.

Schmitt Nathalie N Liu Yang Y Bentebibel Salah-Eddine SE Munagala Indira I Bourdery Laure L Venuprasad K K Banchereau Jacques J Ueno Hideki H Ueno Hideki H

Nature immunology 20140727 9

Understanding the developmental mechanisms of follicular helper T cells (TFH cells) in humans is relevant to the clinic. However, the factors that drive the differentiation of human CD4+ helper T cells into TFH cells remain largely undefined. Here we found that transforming growth factor-β (TGF-β) provided critical additional signals for the transcription factors STAT3 and STAT4 to promote initial TFH differentiation in humans. This mechanism did not appear to be shared by mouse helper T cells. ...[more]

PMID: 25064073

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Project description:Abstract Background The aryl hydrocarbon receptor (AhR) is a critical regulator of the pathogenesis of autoimmune disorders. We aimed to investigate the therapeutic effect of the AhR agonist tapinarof during the development of systemic lupus erythematosus (SLE). Methods MRL/lpr mice were intraperitoneally injected with 1 or 5 mg/kg tapinarof for 6 weeks. Kidney histopathology was evaluated using hematoxylin and eosin (H&E) and Periodic‐Acid‐Schiff (PAS) staining. Immunofluorescence microscopy was performed to detect immune complex renal depositions. Flow cytometry (FCM) analysis was carried out to determine the proportions of T and B cell subsets. Realtime qPCR was used to quantify the expression of Tfh cell‐associated genes. We conducted an in vitro polarization experiment to observe the effect of tapinarof on Tfh differentiation. Western blotting was used to detect the expression of target proteins. Results We found that tapinarof treatment ameliorated lupus phenotypes, including splenomegaly, lymph node enlargement, kidney damages, immune complex deposition, and excessive secretion of antibodies. Additionally, we showed that Treg subpopulation frequencies significantly increased in MRL/lpr mice treated with tapinarof, while the proportion of Th1/Th2 cells was reduced after tapinarof administration. Moreover, tapinarof suppressed Tfh cell differentiation and germinal center (GC) reaction in vivo. The inhibitory effect of tapinarof on Tfh cells was further verified in the in vitro Tfh cell polarization experiment. Realtime qPCR revealed that tapinarof repressed the expression of Tfh signature genes. Mechanistically, tapinarof significantly inhibited the phosphorylation levels of JAK2 and STAT3. The capacity for Tfh differentiation was partially rescued by the STAT3 activator Colivelin TFA. Furthermore, our in vitro Tfh polarization experiments indicated that tapinarof suppressed Tfh cell development in SLE. Conclusions Our data demonstrated that tapinarof modulated the JAK2‐STAT3 pathway to suppress Tfh cell differentiation for the treatment of lupus symptoms in MRL/lpr mice. Tapinarof ameliorates lupus development of MRL/lpr mice. Tapinarof inhibits the differentiation of Tfh cells. Tapinarof modulates JAK2‐STAT3 pathway to suppress Tfh cell differentiation.

Dataset Information

The cytokine TGF-? co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells.

Publications

The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells.

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