Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression

IL-4 plays an important role in the induction of Th2 and Th9 cells, as well as in the inhibition of Th1 cell generation. We show that a combination of IL-4 and TGF-β augments the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFN-γ is present. The T-box–containing transcription factor eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells and is involved in IFN-γ production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFN-γ gene loci. TGF-β is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6-signaling pathway. IFN-γ–producing CD103+ Th1 cells are detected in the intraepithelial lymphocytes of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. To our knowledge, these results represent the first molecular mechanism of IL-4/TGF-β–dependent augmentation of Th1 cell generation and raise the possibility that IL-4 and TGF-β simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions.

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confidence: 99%

“…IFN-g can also prime Th1 cells independent of IL-12 (12). The activation of Stat1 and the subsequent T-bet induction seem to be essential for IFN-g-induced Th1 cell development (11).…”

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confidence: 99%

Identification of a New Pathway for Th1 Cell Development Induced by Cooperative Stimulation with IL-4 and TGF-β

Tofukuji

Kuwahara

Suzuki

et al. 2012

“…However, the cytokine environment in which naive T cells are primed is believed to play the most critical role in regulating commitment to the Th1 lineage (12)(13)(14)(15)(16). Although there is still some debate as to which cytokine-producing pathways are most important for initiating, amplifying, and sustaining the Th1 differentiation process, it is clear that IFN-␥, IL-12, and IL-27 are important (17)(18)(19)(20)(21).…”

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confidence: 99%

Regulation of IFN-γ Production by B Effector 1 Cells: Essential Roles for T-bet and the IFN-γ Receptor

Harris

Goodrich

Gerth

et al. 2005

162

155

This manuscript systematically identifies the molecular mechanisms that regulate the ability of B cells to produce the critical type 1 cytokine, IFN-γ. B cells produce IFN-γ in response to IL-12 and IL-18 and when primed by Th1 cells. We show that development of IFN-γ-producing B cells by either Th1 cells or IL-12/IL-18 is absolutely dependent on expression of the IFN-γR and the T-box transcription factor, T-bet. Interestingly, although T-bet up-regulation in developing B effector 1 (Be1) cells is controlled by IFN-γR-mediated signals, STAT1-deficient B cells up-regulate T-bet and produce IFN-γ, indicating that additional transcriptional activators must be coupled to the IFN-γR in B cells. Finally, we show that although IL-12/IL-18 or IFN-γ-producing Th1 cells are required to initiate transcription of the IFN-γ gene in B cells, sustained expression of IFN-γ and T-bet by B cells is dependent on an IFN-γ/IFN-γR/T-bet autocrine feedback loop. These findings have significant implications, because they suggest that IFN-γ-producing B cells not only amplify Th1 responses, but also imprint a type 1 phenotype on B cells themselves. In the case of immune responses to bacterial or viral pathogens, this B cell-driven autocrine feedback loop is likely to be beneficial; however, in the case of B cell responses to autoantigens, it may result in amplification of the autoimmune loop and increased pathology.

“…It has been reported that IL-18Ra and ST2L are selectively upregulated and expressed by Th1 and Th2 cells, respectively (21)(22)(23)(24)(25). We confirm the association of Th1 cells and high IL-18Ra expression, but we were unable to reproduce that Th2 cells have increased ST2L expression.…”

Section: Discussionmentioning

confidence: 99%

“…IL-18R and IL-33R contain, respectively, a highly regulated primary binding chain IL-18Ra or IL-1R-like 1 (ST2L) and a constitutively expressed IL-18Rb or IL-1R accessory protein (20). The expression of IL-18Ra and ST2L in the human and murine systems has been described to be expressed on Th1 and Th2 cells, respectively (21)(22)(23)(24)(25).…”

Section: D4mentioning

confidence: 99%

IL-1 Family Members IL-18 and IL-33 Upregulate the Inflammatory Potential of Differentiated Human Th1 and Th2 Cultures

Blom

Poulsen

2012

The IL-1 family members IL-1β, IL-18, and IL-33 are potent cytokines in relationship to amplifying the CD4+ T cell cytokine production. To evaluate their impact on in vitro-differentiated human Th1 and Th2 cultures, such cultures were established from naive T cells, purified from healthy blood donors, and reactivated in the presence of IL-1β, IL-18, or IL-33. Interestingly, we observe modifying responses in Th1 and Th2 cultures induced by IL-18 or IL-33 but not by IL-1β, both contributing to amplify production of IL-5, IL-13, and IFN-γ. IL-18 or IL-33 stimulation of Th1 cultures resulted in increased IFN-γ and IL-13 production concurrent with reduced IL-10 gene transcription and secretion even though Th1 cultures, in contrast to IL-18Rα, had low ST2L expression. Furthermore, adding IL-18 to Th1 cultures promoted Tbet mRNA expression and production. Th2 cultures stimulated with IL-18 or IL-33 had an increased IL-5 secretion. Interestingly, E4BP4 gene expression and the percentage of E4BP4+ cells of the recently shown IL-10 transcriptional regulator E4BP4 correlated with IL-10 gene expression and protein secretion in Th1 cultures. Taken together, we report that the IL-1 family “alarmins” IL-18 and IL-33 in addition to amplifying both Th1- and Th2-associated cytokines block production of the regulatory cytokine IL-10 in Th1 cultures.