Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation
Teresa Preglej, Patricia Hamminger, Maik Luu, Tanja Bulat, Liisa Andersen, Lisa Göschl, Valentina Stolz, Ramona Rica, Lisa Sandner, Darina Waltenberger, Roland Tschismarov, Thomas Faux, Thorina Boenke, Asta Laiho, Laura L. Elo, Shinya Sakaguchi, Günter Steiner, Thomas Decker, Barbara Bohle, Alexander Visekruna, Christoph Bock, Birgit Strobl, Christian Seiser, Nicole Boucheron, Wilfried Ellmeier
Teresa Preglej, Patricia Hamminger, Maik Luu, Tanja Bulat, Liisa Andersen, Lisa Göschl, Valentina Stolz, Ramona Rica, Lisa Sandner, Darina Waltenberger, Roland Tschismarov, Thomas Faux, Thorina Boenke, Asta Laiho, Laura L. Elo, Shinya Sakaguchi, Günter Steiner, Thomas Decker, Barbara Bohle, Alexander Visekruna, Christoph Bock, Birgit Strobl, Christian Seiser, Nicole Boucheron, Wilfried Ellmeier
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Research Article Immunology

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation

Abstract

Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1cKO-HDAC2HET) in CD4+ T cells induced a T helper cytotoxic program that was controlled by IFN-γ–JAK1/2–STAT1 signaling. In vitro, activated HDAC1cKO-HDAC2HET CD4+ T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8+ T cells and human CD4+ CTLs. In vivo, murine cytomegalovirus–infected HDAC1cKO-HDAC2HET mice displayed a stronger induction of CD4+ CTL features compared with infected WT mice. Finally, murine and human CD4+ T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4+ CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4+ CTLs.

Authors

Teresa Preglej, Patricia Hamminger, Maik Luu, Tanja Bulat, Liisa Andersen, Lisa Göschl, Valentina Stolz, Ramona Rica, Lisa Sandner, Darina Waltenberger, Roland Tschismarov, Thomas Faux, Thorina Boenke, Asta Laiho, Laura L. Elo, Shinya Sakaguchi, Günter Steiner, Thomas Decker, Barbara Bohle, Alexander Visekruna, Christoph Bock, Birgit Strobl, Christian Seiser, Nicole Boucheron, Wilfried Ellmeier

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Figure 4

An IFN-γ–JAK1/2–STAT1 signaling pathway is required for CD4+ CTL features in HDAC1cKO-HDAC2HET CD4+ T cells.

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An IFN-γ–JAK1/2–STAT1 signaling pathway is required for CD4+ CTL feature...
(A) Histogram overlays depict T-bet, EOMES, RUNX3, and ThPOK expression in naive WT (upper panel), HDAC1cKO-HDAC2HET CD4+ (middle panel) and WT CD8+ T cells (lower panel) activated with anti-CD3/anti-CD28 for 3 days in the presence (solid red line) or absence (control, dotted black line) of IFN-γ–blocking antibodies (α–IFN-γ). (B) Histograms depict p-STAT1 levels in naive WT and HDAC1cKO-HDAC2HET CD4+ T cells activated with anti-CD3/anti-CD28 in the presence of IL-2 and analyzed by flow cytometry at the indicated time points. (C) Histograms depict IFN-γ, granzyme B, T-bet, EOMES, RUNX3, ThPOK, CD8, and CRTAM expression in naive WT and STAT1cKO CD4+ T cells activated with anti-CD3/anti-CD28 for 3 days. During the last 24 hours before analysis, DMSO (control, dotted black line) and the HDACi MS-275 (solid red line) were added. (D) Summary of experiments described in C. Diagrams depict the percentages of CD4+ T cells expressing the indicated cytokines/transcription factors; or WT (DMSO) MFI levels were set as 1, and relative MFI levels in WT (MS-275) and HDAC1cKO-HDAC2HET (DMSO/MS-275) CD4+ T cells are shown. Each symbol indicates 1 independent biological sample. Horizontal bars indicate the mean. *P < 0.05, **P < 0.01, and ***P < 0.001 (1-way ANOVA analysis followed by Tukey’s multiple-comparisons test). (A–C) Numbers indicate the percentage of cells in the respective quadrants and gates or, as indicated, the MFI. The dotted vertical lines indicate the peak of the WT histogram (for MFI), while the vertical solid lines indicate the gating region for the percentage of cells. Data are representative of at least 5 (A) or 4 (B–D) mice that were analyzed in at least 3 (A, C, and D) or 2 (B) independent experiments.