title: Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Gaku
authors.initials: G
authors.lastname: Tsuji
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okiyama
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Vadim A
authors.initials: VA
authors.lastname: Villarroel
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md. Electronic address: katzs@od.niams.nih.gov.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Katz
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003877:Dermatitis, Contact / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011743:Pyrimidines; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C572255:ricolinostat
keywords: CD8 T cell; contact hypersensitivity; graft-versus-host-disease; histone deacetylase 6