A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Histone deacetylases 1 and 2 restrain CD4(+) cytotoxic T lymphocyte differentiation
Tekijät: 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
Kustantaja: AMER SOC CLINICAL INVESTIGATION INC
Julkaisuvuosi: 2020
Journal: JCI Insight
Tietokannassa oleva lehden nimi: JCI INSIGHT
Lehden akronyymi: JCI INSIGHT
Artikkelin numero: ARTN e133393
Vuosikerta: 5
Numero: 4
Sivujen määrä: 18
DOI: https://doi.org/10.1172/jci.insight.133393
Verkko-osoite: https://doi.org/10.1172/jci.insight.133393
Rinnakkaistallenteen osoite: 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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
