Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells

Abstract

Summary T‐cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor‐β1 (TGF‐β1) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin‐6 (IL‐6) and IL‐4, IL‐12 can inhibit the development of TGF‐β1‐induced Foxp3‐expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL‐12, although there is a parallel pathway involving T box expressed in T cells (T‐bet), and cells from mice double‐deficient in STAT4 and T‐bet are refractory to the inhibition of aTreg‐cell development by IL‐12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL‐12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL‐2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4−/− mice, compared with wild‐type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg‐cell development.

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

“…2D). Because insufficient induction of pSTAT4 during CD4 T-cell activation can lead to T-cell anergy or induction of regulatory T cells (14), we hypothesized that testosterone may increase the threshold of IL-12 required to induce Th1 differentiation. CD4 T cells were cultured under Th1 polarizing conditions with increasing concentrations of IL-12 either in the presence of 1 ng/mL R1881 or vehicle control, and the expression of T-bet was assessed 3 d later.…”

STAT4 Regulates the CD8+ Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr−/− Mice

“…It is well-known that STAT4 is a transcription factor involved in the differentiation of Th1 cells 6 and negative regulation of CD4 + Treg generation 8;27 . Here we hypothesized that STAT4 might be also important as a negative regulator for the differentiation of CD8 + Tregs upon Treg stimulating conditions in vitro .…”

“…STAT4 and the T-box transcription factor (T-bet) are key transcription factors that support the differentiation of Th1 cells. Importantly, the expression of STAT4 also suppresses the expansion of Foxp3 + CD4 + Tregs 8 . Thus STAT4 is involved in the regulation of a delicate balance between pro-inflammatory and suppression arms of the immune response.…”

STAT4 gene polymorphism in patients after renal allograft transplantation

“…STAT4 protein comprises an N-terminal domain that plays an important role in phosphorylation and nuclear translocation, as well as a four-stranded helical coiled coil that is implicated in protein–protein interaction and nuclear import and export [2]. STAT4 plays a significant role in the regulation of natural killer (NK) cells, CD8+ T cells, and Th1 function, as well as in the differentiation of B cells and regulatory T (Treg) cells [3, 4]. STAT4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages, and plays a significant role in the signalling pathway of several important cytokines [5, 6].…”