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Review
. 2012 Nov;42(11):2827-33.
doi: 10.1002/eji.201242433. Epub 2012 Oct 8.

STAT6-dependent and -independent mechanisms in Th2 polarization

Elisabeth Maier  1 , Albert Duschl, Jutta Horejs-Hoeck
Affiliations
Free PMC article
Review

STAT6-dependent and -independent mechanisms in Th2 polarization

Elisabeth Maier et al. Eur J Immunol. 2012 Nov.
Free PMC article

Abstract

Th2 cells play a key role in directing immune responses against helminths. Additionally, Th2 cells are crucial for many types of allergic reactions. Whereas the molecular mechanisms underlying the differentiation of other types of Th cells are well understood, Th2 differentiation is still a controversial topic. IL-4 and its downstream transcription factor signal transducer and activator of transcription (STAT)6 are well-known key mediators in Th2 differentiation. The fact that Th2 cells themselves are the most potent source of IL-4 suggests that additional mechanisms promoting the initiation of Th2 differentiation exist. This article gives an overview on STAT6-dependent and -independent mechanisms involved in the process of Th2 polarization, including Notch, mTORC2, IL-2/STAT5, and Wnt. Furthermore, we emphasize the role of STAT6 not only as a transcriptional activator promoting Th2 development, but also in fine-tuning alternative signaling pathways which are involved in the initiation of Th2 polarization.

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Figures

Figure 1
Figure 1
Signaling pathways in Th2 differentiation. Binding of IL-4 to the IL-4 receptor results in the phosphorylation and dimerization of signal transducer and activator of transcription 6 (STAT6). STAT6 dimers translocate into the nucleus where they promote expression of the Th2 master regulator GATA-binding protein 3 (GATA3). GATA3 is translated from two distinct transcripts termed GATA3–1a and GATA3–1b that derive from two different promoters. Activated STAT6 induces the expression of GATA3 from both promoters. GATA3, in turn, binds to and modifies the IL5–IL13–IL4 locus, which results in enhanced expression of Th2-related cytokines. Additionally, several other pathways facilitate Th2 differentiation. Suppressor of cytokine signaling 5 (SOCS5) acts as a repressor of STAT6-mediated transcription. The mTORC2-signaling complex supports IL-4/STAT6 signaling by inhibiting SOCS5. IL-2 contributes to Th2 differentiation by activating STAT5A, which induces transcription of IL-4 in a GATA3-independent way. Upon activation of Notch, the intracellular Notch-domain forms a signaling complex with RBPJ (recombination-signal-binding protein for immunoglobulin-κ J region) and Mastermind-like 1 (MAML-1), which induces transcription from Gata3–1a. T-cell factor 1 (TCF-1) and β-catenin induce GATA3–1b transcription in a STAT6-independent way. Activation of GATA3 by TCF-1 is counterregulated by dominant-negative isoforms of TCF-1 (dn TCF-1) which are also expressed in naïve T cells. Low concentrations of IL-4 inhibit the expression of the dominant-negative TCF-1 isoforms thereby promoting TCF-1-induced GATA3 expression and Th2 polarization.
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