Histone deacetylases 1 and 2 restrain CD4(+) cytotoxic T lymphocyte differentiation
Hamminger P; Decker T; Tschismarov R; Visekruna A; Faux T; Sandner L; Andersen L; Sakaguchi S; Waltenberger D; Bulat T; Boucheron N; Luu M; Boenke T; Bohle B; Strobl B; Seiser C; Preglej T; Goschl L; Rica R; Laiho A; Steiner G; Stolz V; Elo LL; Ellmeierl W; Bock C
Histone deacetylases 1 and 2 restrain CD4(+) cytotoxic T lymphocyte differentiation
Hamminger P
Decker T
Tschismarov R
Visekruna A
Faux T
Sandner L
Andersen L
Sakaguchi S
Waltenberger D
Bulat T
Boucheron N
Luu M
Boenke T
Bohle B
Strobl B
Seiser C
Preglej T
Goschl L
Rica R
Laiho A
Steiner G
Stolz V
Elo LL
Ellmeierl W
Bock C
Lataukset:
AMER SOC CLINICAL INVESTIGATION INC
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042823620
https://urn.fi/URN:NBN:fi-fe2021042823620
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]