Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation
Open accessAbstract
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-γ–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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T cell-specific deletion of class I HDACs HDAC1 and HDAC2 triggers expression of genes associated with cytolytic activity even in CD4+ T cells.
“Our recent report demonstrated that the T cell-specific deletion of class I HDACs HDAC1 and HDAC2 (a deletion of two Hdac1 alleles and one Hdac2 allele) triggered the expression of genes associated with cytolytic activity even in CD4+ T cells39.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [39]
Pentanoate induces in vitro CD4+ CTL differentiation in human CD4+ T cells with a similar phenotype.
“Furthermore, pentanoate was also able to induce in vitro CD4+ CTL differentiation in human CD4+ T cells with similar phenotype39”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [39]
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References 59 · Cited by 36
Research works printed but not linked: 1
- Hagelkruys A, et al. A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog. Development. 2014;141(3):604-616. · DOI · Paper page
- Authors
- Preglej, T., Hamminger, P., Luu, M., Bulat, T., Andersen, L., Göschl, L., Stolz, V., Rica, R., Sandner, L., Waltenberger, D., Tschismarov, R., Faux, T., Boenke, T., Laiho, A., Elo, L. L., Sakaguchi, S., Steiner, G., Decker, T., Bohle, B., Visekruna, A., Bock, C., Strobl, B., Seiser, C., Boucheron, N., & Ellmeier, W.
- Affiliations
- Medical University of Vienna (AT)
- Philipps University of Marburg (DE)
- University of Veterinary Medicine Vienna (AT)
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
- University of Vienna (AT)
- Åbo Akademi University (FI)
- Austrian Academy of Sciences (AT)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation (AT)
- Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology,
- Corresponding author
- Ellmeier, Wilfried
- ORCID
- Preglej, Teresa
- Luu, Maik
- Bulat, Tanja
- Andersen, Liisa
- Göschl, Lisa
- Stolz, Valentina
- Sandner, Lisa
- Waltenberger, Darina
- Tschismarov, Roland
- Faux, Thomas
- Boenke, Thorina
- Laiho, Asta
- Elo, Laura L.
- Sakaguchi, Shinya
- Steiner, Günter
- Decker, Thomas
- Bohle, Barbara
- Visekruna, Alexander
- Bock, Christoph
- Strobl, Birgit
- Seiser, Christian
- Boucheron, Nicole
- Ellmeier, Wilfried
- Venue
- JCI Insight
- Published
- 2020-02-27
- Volume
- 5
- Issue
- 4
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC7101144
- OpenAlex
- W3007489435
- Cited by
- 36
- References
- 59
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 5
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UTUPub (University of Turku) (submittedVersion)
- Funders
- Austrian Science Fund (SFB-F70,W1212,P19930,P23641,P26193,P27747,P28705)
- Horizon 2020 (675395,115142)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- histone deacetylase, HDAC1, HDAC2, cytotoxic CD4+ T cells, T cell differentiation, interferon-gamma signaling, JAK1/2, STAT1, cytomegalovirus infection, short-chain fatty acids, histone deacetylase inhibitors, CD8+ effector T cells, T helper cells
- MeSH terms
- Animals, Cell Differentiation, Fatty Acids, Humans, T-Lymphocytes, Cytotoxic, Signal Transduction, CD4-Positive T-Lymphocytes, Up-Regulation, Mice, Knockout, Mice, Histone Deacetylase 1, Histone Deacetylase 2
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