A1 Refereed original research article in a scientific journal
Histone deacetylases 1 and 2 restrain CD4(+) cytotoxic T lymphocyte differentiation
Authors: Preglej T, Hamminger P, Luu M, Bulat T, Andersen L, Goschl L, Stolz V, Rica R, Sandner L, Waltenberger D, Tschismarov R, Faux T, Boenke T, Laiho A, Elo LL, Sakaguchi S, Steiner G, Decker T, Bohle B, Visekruna A, Bock C, Strobl B, Seiser C, Boucheron N, Ellmeierl W, Ellmeierl W
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Publication year: 2020
Journal: JCI Insight
Journal name in source: JCI INSIGHT
Journal acronym: JCI INSIGHT
Article number: ARTN e133393
Volume: 5
Issue: 4
Number of pages: 18
DOI: https://doi.org/10.1172/jci.insight.133393
Web address : https://doi.org/10.1172/jci.insight.133393
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/46668111
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 (HDAC1(cKO)-HDAC2(HET)) in CD4(+) T cells induced a T helper cytotoxic program that was controlled by IFN-gamma-JAK1/2-STAT1 signaling. In vitro, activated HDAC1(cKO)-HDAC2(HET) 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 HDAC1(cKO)-HDAC2(HET) 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.
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