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TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes

Abstract

Naïve T cells differentiate into effector cells upon stimulation with antigen, a process that is accompanied by changes in the chromatin structure of effector cytokine genes. Using histone acetylation to evaluate these changes, we showed that T cell receptor (TCR) stimulation results in early activation of the genes encoding both interleukin 4 and interferon-γ. We found that continued culture in the presence of polarizing cytokines established a selective pattern of histone acetylation on both cytokine genes; this correlated with restricted access of the transcription factor NFAT1 to these gene regulatory regions as well as mutually exclusive gene expression by the differentiated T cells. Our data point to a biphasic process in which cytokine-driven signaling pathways maintain and reinforce chromatin structural changes initiated by the TCR. This process ensures that cytokine genes remain accessible to the relevant transcription factors and promotes functional cooperation of the inducible transcription factor NFAT with lineage-specific transcription factors such as GATA-3 and T-bet.

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Acknowledgements

We thank members of the laboratory for critical reading of the manuscript and valuable discussions. Supported by grants from the National Institutes of Health (to A. R. and L. H. G.), a gift from the G. Harold and Leila Y. Mathers Charitable Foundation (to L. H. G.), the Cancer Research Institute (to O. A.), the National Institutes of Health (to D. L.) and the Leukemia Society and a grant from the Burroughs Wellcome Fund (to S. J. S.).

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Correspondence to Anjana Rao.

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Figure 1: No detectable histone acetylation at Il4 and Ifng regulatory regions of naïve T cells.
Figure 2: Selective histone acetylation at Il4 and Ifng regulatory regions in differentiated T cells.
Figure 3: Nonselective histone acetylation and restriction enzyme accessibility at Il4 regulatory elements at an early stage of T cell differentiation.
Figure 4: The selective histone acetylation pattern is established by the polarizing cytokines.
Figure 5: Histone acetylation at gene regulatory elements in wild-type and STAT6-deficient T cells, and in vivo binding of STAT6 and NFAT1 to Il4 regulatory regions.
Figure 6: Functional cooperation between GATA-3 and NFAT1 and inducible binding of GATA-3 to the Il4 enhancer.
Figure 7: Histone acetylation in wild-type and T-bet–deficient T cells, and in vivo binding of NFAT1 to the Ifng promoter.