T cells: Shaping Il4 gene expression

Abstract

(TH2)-associated cytokine genes — interleukin-4 (IL4), IL5 and IL13 — is controlled by the TH2 cell master regulator GATA-binding protein 3 (GATA3). However, the molecular basis of GATA3-mediated gene regulation during TH2 cell development is unclear and controversial. Tanaka et al. now show that binding of GATA3 to DNase I hypersensitive site 2 (HS2) in the second intron of the Il4 locus is specifically required for chromosomal modifications at this locus that allow transcription of Il4. Numerous regulatory elements in the TH2 cytokine locus have been identified, but whether TH2-associated cytokine expression is controlled by a single element or by the coordinated activity of multiple elements is not known. To address this issue, the authors generated a series of mutant mice that lack each hypersensitive element in the Il4–Il13 locus and assessed the effect of each deletion on cytokine production. TH2 cells from mice that lack HS2 produced the lowest levels of IL-4 following activation, whereas the expression of other TH2-type cytokines by these cells was similar to wild-type TH2 cells. These data suggest a specific role for HS2 in IL-4 expression. Deletion of other regulatory elements also impaired IL-4 expression, but to a lesser extent, suggesting that multiple elements are required for complete lineage-specific expression of IL-4. By contrast, naive T cells that lack the conserved GATA3-response element (GCRE) in the Il13 locus gave rise to wild-type numbers of IL-4-producing T cells but few IL-13-producing T cells in TH2 cell-inducing conditions, indicating that this element regulates Il13 transcription. Next, the authors assessed whether GATA3 is linked to the function of the HS2 enhancer. Unlike in wild-type TH1 cells, overexpression of GATA3 in HS2-deficient TH1 cells T c e l l s

DOI: 10.1038/nri2908

Cite this paper

@article{Leavy2011TCS, title={T cells: Shaping Il4 gene expression}, author={Olive Leavy}, journal={Nature Reviews Immunology}, year={2011}, volume={11}, pages={3-3} }