Overlapping and Distinct Roles of STAT4 and T-bet in the Regulation of T Cell Differentiation and Allergic Airway Inflammation

Abstract

T-bet and STAT4 play critical roles in helper T cell differentiation, especially for Th1 cells. However, it is still unknown about the relative importance and redundancy of T-bet and STAT4 for Th1 differentiation. It is also unknown about their independent role of T-bet and STAT4 in the regulation of allergic airway inflammation. In this study, we addressed these issues by comparing T-bet-deficient (T-bet−/−) mice, STAT4−/− mice, and T-bet- and STAT4-double-deficient (T-bet−/−STAT4−/−) mice on the same genetic background. Th1 differentiation was severely decreased in T-bet−/− mice and STAT4−/− mice as compared with that in wild-type mice, but Th1 differentiation was still observed in T-bet−/− mice and STAT4−/− mice. However, Th1 cells were hardly detected in T-bet−/−STAT4−/− mice. In contrast, the maintenance of Th17 cells was enhanced in T-bet−/− mice but was reduced in STAT4−/− mice and T-bet−/−STAT4−/− mice. In vivo, Ag-induced eosinophil and neutrophil recruitment into the airways was enhanced in T-bet−/− mice but was attenuated in STAT4−/− mice and T-bet−/−STAT4−/− mice. Ag-induced IL-17 production in the airways was also diminished in STAT4−/− mice and T-bet−/−STAT4−/− mice. These results indicate that STAT4 not only plays an indispensable role in T-bet-independent Th1 differentiation but also is involved in the maintenance of Th17 cells and the enhancement of allergic airway inflammation.

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

“…Previous reports have correlated decreased allergic inflammation in Stat4 )/) mice with decreases in IL-17 production and local chemokine production. 31,32 Indeed, these two observations may be linked because IL-17 is a potent inducer of chemokine production. 34 It is possible that Treg cells normally contribute to this aspect by regulating IL-17 production from Th17 or other proinflammatory cells.…”

“…31,32 The mechanism of this defect is still unclear but appears to involve decreased IL-17 and chemokine production. We speculated that these phenotypes might arise from altered Treg-cell generation.…”

Enteric pathogens and gut function: Role of cytokines and STATs

“…Although Th17 cells produce a distinct profile of cytokines and develop along a separate pathway from Th1 cells, both STAT4 and T-bet are needed for the differentiation of Th17 cells in response to IL-23. [20][21][22] TGFb is required for Th17 development, but suppresses Th1 development by inhibiting STAT4 and T-bet signaling 23 as well as Th2 development by reducing GATA-3 expression. 24 In addition, IL-12, working through STAT4, also inhibits the development of Tregs that are critical to the mucosal immune cell tolerance needed for homeostasis.…”

Signal Transduction and TH17 Cell Differentiation

“…[19]. Lastly, and most recently reported, CD4 + CD62L High cells from Tbet −/− and control mice at 3 and 7 days post-stimulation had similar fractions of Th17 cells [20].…”