The DOI matches its Crossref record; 63 of the 64 references it cites were found in a registry or an index.
A Novel Role for Histone Deacetylase 6 in the Regulation of the Tolerogenic STAT3/IL-10 Pathway in APCs
Open accessAbstract
APCs are critical in T cell activation and in the induction of T cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. In this study, to our knowledge we show for the first time that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells results in diminished production of the immunosuppressive cytokine IL-10 and induction of inflammatory APCs that effectively activate Ag-specific naive T cells and restore the responsiveness of anergic CD4+ T cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising amino acids 503–840 as being required for HDAC6 interaction with STAT3. Furthermore, by re–chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation—but no changes in STAT3 acetylation—as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance toward T cell immunity.
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“STAT3–HDAC6 transcriptionally upregulates IL-10, preventing effective Ag-specific CD4+ T cell activation in tumor-bearing mice”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Cheng et al., 2014
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“use of a HDAC inhibitor enabled effective T cell priming and antitumor response”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Cheng et al., 2014
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HDAC6 is a microtubule-associated deacetylase
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Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
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Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces
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Noonepalle, S. K. R., Gracia-Hernandez, M., Aghdam, N., Berrigan, M. J., Coulibaly, H., Li, X., Delgado, C. Z., Pletcher, A., Weselman, B., Palmer, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.27019262
Self-citationHDAC6 Promotes Host Defense Against Chlamydial Lung Infections by Regulating M2-Th2 Responses
Yu, J., Yang, S., Zha, X., Tuo, Y., Sun, R., Zhang, H., Tan, L., & Bai, H. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27073009
Shen, S. (2026) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2026.2676080
Hu, H., Liu, Y., Li, Y., Su, H., Liu, S., He, Q., Liao, W., Xu, T., Zhang, H., & Zheng, H. (2026) · Comparative Biochemistry and Physiology Part D Genomics and Proteomics · doi:10.1016/j.cbd.2026.101872
Maiti, K., Chakraborty, D., Ponnusamy, C. S., Gnanasekar, H., Ravindran, N., Sridharan, B., & Velusamy, M. (2026) · Journal of Molecular Modeling · doi:10.1007/s00894-026-06893-3
Metadata
- Authors
- Cheng, F., Lienlaf, M., Wang, H.-W., Perez-Villarroel, P., Lee, C., Woan, K., Rock-Klotz, J., Sahakian, E., Woods, D., Pinilla-Ibarz, J., Kalin, J., Tao, J., Hancock, W., Kozikowski, A., Seto, E., Villagra, A., & Sotomayor, E. M.
- Affiliations
- Moffitt Cancer Center (US)
- Department of Immunology and Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL 33612
- Johns Hopkins University (US)
- University of Illinois Chicago (US)
- University of Pennsylvania (US)
- Corresponding author
- Cheng, Fengdong
- Lienlaf, Maritza
- Woan, Karrune
- Sahakian, Eva
- Woods, David
- Tao, Jianguo
- Villagra, Alejandro
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-09
- Volume
- 193
- Issue
- 6
- Pages
- 2850-2862
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4157123
- OpenAlex
- W2151850046
- Cited by
- 106
- References
- 64
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 12 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 15 · 2019: 12 · 2018: 11 · 2017: 6 · 2016: 8 · 2015: 5
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R21CA184612, R01CA087583, CA134807, T32CA115308, R01CA134807, R21CA153246, R01CA100850, CA87583, CA100850, P30CA076292)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- HDAC6, STAT3, IL-10, antigen-presenting cells, dendritic cells, macrophages, T cell tolerance, STAT3 phosphorylation, epigenetic regulation, HDAC6 inhibitors, T cell activation
- MeSH terms
- Histone Deacetylase 6, Acetylation, Animals, Antigen-Presenting Cells, Cell Line, Dendritic Cells, Gene Expression Regulation, Histone Deacetylases, Immune Tolerance, Inflammation, Lymphocyte Activation, Macrophages, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, Oligopeptides, Phosphorylation, Promoter Regions, Genetic, Recombinant Proteins, Transcription, Genetic, CD4-Positive T-Lymphocytes, Gene Expression, Interleukin-10, Protein Structure, Tertiary, Mice, Knockout, RNA Interference, RNA, Small Interfering, Chromatin Immunoprecipitation, STAT3 Transcription Factor, Mice, Histone Deacetylase Inhibitors
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