Antigen-presenting cell-derived IL-6 restricts the expression of GATA3 and IL-4 by follicular helper T cells

Abstract

Follicular helper T cells (Tfh) support high-affinity Ab production by germinal center B cells through both membrane interactions and secretion of IL-4 and -21, two major cytokines implicated in B-cell survival and Ab class switch. Tfh-2 cells recently emerged in humans as a strong IL-4 producer Tfh cell subset implicated in both autoimmune and allergic diseases. Although the molecular mechanisms governing Tfh cell differentiation from naive T cells have been widely described, much less is known about the regulation of cytokine secretion by mouse Tfh-2 cells. The purpose of our study was to evaluate the role of dendritic cell-derived IL-6 in fine-tuning cytokine secretion by Tfh cells. Our results demonstrate that priming of Th cells by IL-6-deficient antigen-presenting dendritic cells preferentially leads to accumulation of a subset of Tfh cells characterized by high expression of GATA3 and IL-4, associated with reduced production of IL-21. STAT3-deficient Tfh cells also overexpress GATA3, suggesting that early IL-6/STAT3 signaling during Tfh cell development inhibits the expression of a set of genes associated with the Th2 differentiation program. Overall, our data indicate that IL-6/STAT3 signaling restrains the expression of Th2-like genes in Tfh cells, thus contributing to the control of IgE secretion in vivo.

TNF-α–induced protein 3 levels in lung dendritic cells instruct T H 2 or T H 17 cell differentiation in eosinophilic or neutrophilic asthma

“…43,44 IL-6 inhibits T H 2 immunity either directly by inhibiting GATA-3 expression or indirectly by restricting IL-4 expression by follicular T H cells. 47 IL-12 strongly promotes T H 1 differentiation and thereby hampers T H 2 differentiation. 43 Ablating TNFAIP3 expression in DCs increased AHR on chronic exposure to HDM, whereas levels of the AHR-inducing Tnfaip3 WT A C D cytokine IL-13 was similar between knockout and WT mice; however, IL-17 levels are specifically increased in mice lacking TNFAIP3 in DCs.…”

Determination of T Follicular Helper Cell Fate by Dendritic Cells

“…However, other studies suggest that, rather than driving early Tfh cell differentiation, DC-derived IL-6 instead fine-tunes the phenotype of newly primed Tfh cells, with other cell types producing the IL-6 that is required for early Tfh differentiation. Using adoptively transferred IL-6-deficient antigen-pulsed DCs, Andris and colleagues show that DC-derived IL-6 has no impact on Tfh cell frequencies or CXCR5, PD1 and BCL6 expression ( 96 ). This is in line with a report from Chen et al who, using mixed bone marrow chimeras, report that IL-6 deficiency in radio-resistant (such as stromal cells) but not radio-sensitive hematopoietic cells (such as DCs), impacts CXCR5 and BCL6 expression in Tfh cells ( 62 ).…”

Preoperative Th1/Th2 and related cytokines: Prediction value in postoperative febrile UTI after ureteroscopy in patients with ureteral calculi

“…29 By contrast, IL-4 can enhance the expression level of GATA3, a transcription factor critical for both IL-4 production and Th2 cell differentiation. 30 To further explore the significance of the Th1/Th2 balance, we used ELISA to determine the expression levels of Th1/Th2 cytokines and applied qRT-PCR to detect the mRNA expression of T-bet and GATA3. We found that patients with postoperative febrile UTI had significantly higher levels of Th2-related cytokines (IL-4, IL-10 and IL-5) and GATA3 than those without postoperative febrile UTI, but no difference was found in the level of Th1-related cytokines (IFN-γ, IL-2 and TNF-α) and T-bet.…”