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Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes

Nature Immunology volume 4, pages 78–86 (2003)Cite this article

Abstract

CD4+ T cell priming under T helper type I (TH1) or TH2 conditions gives rise to polarized cytokine gene expression. We found that in these conditions human naive T cells acquired stable histone hyperacetylation at either the Ifng or Il4 promoter. Effector memory T cells showed polarized cytokine gene acetylation patterns in vivo, whereas central memory T cells had hypoacetylated cytokine genes but acquired polarized acetylation and expression after appropriate stimulation. However, hypoacetylation of the nonexpressed cytokine gene did not lead to irreversible silencing because most TH1 and TH2 cells acetylated and expressed the alternative gene when stimulated under opposite TH conditions. Such cytokine flexibility was absent in a subset of TH2 cells that failed to up-regulate T-bet and to express interferon-γ when stimulated under TH1 conditions. Thus, most human CD4+ T cells retain both memory and flexibility of cytokine gene expression.

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Figure 1: Kinetics of cytokine production and histone H3 acetylation at cytokine gene promoters in nonpolarized, TH1 and TH2 cell lines.
Figure 2: Histone H3 acetylation at cytokine gene promoters in nonpolarized, TH1 and TH2 clones derived from naive T cells in vitro.
Figure 3: Histone acetylation pattern and differentiation potential of central memory T cells.
Figure 4: Correlation between histone acetylation at cytokine gene promoters and cytokine production in freshly isolated CRTh2+ and CCR5+ effector memory T cells.
Figure 5: Maintenance of the histone acetylation pattern and cytokine-producing capacity of effector memory T cells after stimulation in nonpolarizing conditions.
Figure 6: Cytokine flexibility of TH1 and TH2 clones generated in vitro from naive T cells.
Figure 7: Cytokine flexibility of effector memory T cells.
Figure 8: GATA-3 and T-bet as determinants of flexibility in effector memory T cells.

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Acknowledgements

We thank D. Jarrossay for cell sorting; members of Natoli's lab and of Amaxa Biosystems GmbH for help with transfection experiments; and A. Gett and C. Mackay for critical reading and suggestions. Supported, in part, by the European Community (contract number QLK2-CT-201-01205); the San Salvatore Foundation (M.M.) and the Helmut Horten Foundation (A.L.).

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  1. Institute for Research in Biomedicine, Via Vincenzo Vela 6, Bellinzona, CH-6500, Switzerland

    Mara Messi, Isabella Giacchetto, Antonio Lanzavecchia, Gioacchino Natoli & Federica Sallusto

  2. R&D Center, BML, 1361-1 Matoba, Kawagoe, 350-1101, Saitama, Japan

    Kinya Nagata

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Web Fig. 1.

Increased histone acetylation and cytokine production upon secondary stimulation. TH1 and TH2 cell lines, which were stimulated once or twice in polarizing conditions, were analyzed for histone acetylation (a) and cytokine production upon PMA-iono stimulation (b). (PDF 129 kb)

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Messi, M., Giacchetto, I., Nagata, K. et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nat Immunol 4, 78–86 (2003). https://doi.org/10.1038/ni872

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