Transcriptional regulation of Th1/Th2 polarization

doi:10.1016/S0167-5699(00)01712-6

Immunology Today

Volume 21, Issue 10, 1 October 2000, Pages 479-483

Immunology Today

https://doi.org/10.1016/S0167-5699(00)01712-6 Get rights and content

Abstract

The two polarized T helper (Th) subsets Th1 and Th2 are identified by their signature cytokines, interferon γ (IFN-γ) and interleukin 4 (IL-4) respectively. Understanding the transcriptional regulation of cytokine expression is therefore critical for elucidating the process of Th cell differentiation. Ubiquitous and tissue-specific transcription factors, as well as chromatin remodeling of genomic loci have been implicated in IL-4 and IFN-γ regulation. We propose a model of Th1/Th2 polarization based on the balance between Th1- and Th2-specific transcription factors.

Section snippets

Cytokines regulate Th cell differentiation

The polarized subsets Th1 and Th2 both develop from the same Th precursor (Thp) and differentiate into the two phenotypes via a complex developmental process. The dose of antigen, strength of signal through the T-cell receptor (TCR) and costimulation all influence the initiation of Th differentiation2, 4. An important insight was obtained from the observations that the antigen-activated naive Thp cell can be induced to differentiate into the Th1 or Th2 lineage in vitro by the addition of

Transcriptional regulation of cytokine gene expression

Signals through the TCR as well as through cytokine receptors elicit a complex series of molecular interactions that culminate in the transcription of cytokine genes. These signal transduction cascades have emerged as important regulators of Th differentiation but are beyond the scope of this article (reviewed in Ref. 10). Faithful transcription of genes is orchestrated by the cooperative interactions of multiple ubiquitous and cell-type-specific transcription factors, bound to multiple

Ubiquitous and Th2-specific factors mediate IL-4 expression

IL-4 production is tightly regulated and the cytokine is expressed in a subset of immune cells namely Th2 cells, mast cells, NK T cells, basophils, eosinophils and ãä T cells. The quest to delineate the molecular basis for cell-specific and activation-dependent IL-4 expression led several groups to investigate the promoter region of the IL-4 gene (Reviewed in 13, 14, 15). It was shown that 87 bp of sequence upstream of the transcription initiation site was sufficient for TCR-inducible and

Long range regulatory elements and chromatin structure in IL-4 expression

In addition to the cooperative assembly of multiple known and as yet unknown factors and cofactors necessary for IL-4 expression, recent evidence for regulated changes in chromatin structure and the role of distant control regions (for example, enhancers and locus control regions) during Th differentiation has added a further dimension to this model of Th2 polarization (reviewed in 13, 29). Researchers were prompted to examine the remodeling of the chromatin architecture at cytokine loci in

Regulation of IFN-γ and commitment to Th1 differentiation

Complementary to chromatin changes at the IL-4 locus during Th2 differentiation, specific changes occur at the IFN-γ locus in the course of Th1 commitment. DNAse I HSs have been observed in the first and third introns of the IFN-γ gene³² (Fig. 2b). In addition, the locus is hypomethylated in Th1 but not Th2 cells32, 37. Although 8.6 kb of genomic sequence can direct T cell-specific expression of IFN-γ, the IFN-γ promoter has not yet been well characterized and the Th1-specific cis-elements

Striking a balance: T-bet and GATA3

We propose a model for Th1/Th2 polarization that involves a balance between the Th1-specific T-bet and the Th2-specific GATA3 (Fig. 3). The naive Thp cell receives signals through the TCR and costimulatory molecules. If the conditions at the time of activation favor the initiation of Th1 differentiation, for example, IL-12-induced signaling via Stat4, T-bet is induced and promotes Th1 lineage commitment. However, if GATA3 is induced via Stat6 activation, the Th cell is driven down a Th2 pathway

Acknowledgements

We thank Andrea Wurster for critical reading of the manuscript and thoughtful discussions. J.R. is supported by a Fogarty International Fellowhip, S.J.S. is supported by a National Research Service Award, and L.H.G. is supported by NIH grants AI48126, AI31541 and AI43953 and by a Multiple Sclerosis Society grant RG2822A1.