Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation

Gaku Tsuji, Naoko Okiyama, Vadim A. Villarroel, Stephen I. Katz

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background Broad-spectrum histone deacetylase (HDAC) inhibitors are useful in the treatment of allergic and autoimmune diseases and malignancy. However, use of more specific HDAC inhibitors might limit the toxicities caused by HDAC inhibition. HDAC6, a member of the HDAC family, is highly expressed on CD8 T cells and has been shown to regulate immune responses through interactions between T cells and antigen-presenting cells. However, the mechanism by which HDAC6 inhibition affects the activation and functions of CD8 T cells is unclear. Objectives We investigated the role or roles of HDAC6 in CD8 T-cell activation and functions during skin inflammation in vitro and in vivo and examined the mechanism by which HDAC6 inhibition modifies T-cell receptor signaling in vitro. Methods We assessed the clinical and biological effects of ACY-1215, an HDAC6-specific inhibitor, by using murine CD8 T cell-related skin disease models, including contact hypersensitivity (CHS) and experimental graft-versus-host disease (GVHD)-like disease. Results ACY-1215, an HDAC6 inhibitor, prevented the development of CHS and GVHD-like disease in vivo by modulating CD8 T-cell activation and functions; abrogated the induction of effector T cells from naive CD8 T cells by means of anti-CD3/CD28 antibody- or antigen-specific stimulation in vitro; and enhanced the binding of acetylated heat shock protein 90 to lymphocyte-specific protein tyrosine kinase in vitro, disrupting lymphocyte-specific protein tyrosine kinase phosphorylation and leading to impairment of the mitogen-activated protein kinase pathway. Conclusion HDAC6, a key modifier of T-cell receptor signaling, might represent a novel target for the treatment of CD8 T cell-related skin diseases, including CHS and GVHD.

Original languageEnglish
Pages (from-to)1228-1239
Number of pages12
JournalJournal of Allergy and Clinical Immunology
Volume135
Issue number5
DOIs
Publication statusPublished - May 1 2015
Externally publishedYes

Fingerprint

Histone Deacetylases
Inflammation
T-Lymphocytes
Skin
Contact Dermatitis
Graft vs Host Disease
Histone Deacetylase Inhibitors
T-Cell Antigen Receptor
Skin Diseases
Protein-Tyrosine Kinases
Lymphocytes
HSP90 Heat-Shock Proteins
Viral Tumor Antigens
Antigen-Presenting Cells
Mitogen-Activated Protein Kinases
Autoimmune Diseases
Phosphorylation
Antigens
In Vitro Techniques
Antibodies

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation. / Tsuji, Gaku; Okiyama, Naoko; Villarroel, Vadim A.; Katz, Stephen I.

In: Journal of Allergy and Clinical Immunology, Vol. 135, No. 5, 01.05.2015, p. 1228-1239.

Research output: Contribution to journalArticle

Tsuji, Gaku ; Okiyama, Naoko ; Villarroel, Vadim A. ; Katz, Stephen I. / Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 135, No. 5. pp. 1228-1239.
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