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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:135

Article

Tsuji, Gaku¹  Okiyama, Naoko¹  Villarroel, Vadim A.¹  Katz, Stephen I.¹ 

[1] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

关键词: CD8 T cell;    histone deacetylase 6;    contact hypersensitivity;    graft-versus-host-disease;   

DOI  :  10.1016/j.jaci.2014.10.002

来源: Elsevier

【 摘 要 】

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 ACY1215, an HDAC6-specific inhibitor, by using murine CD8 T cellrelated 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 mitogenactivated protein kinase pathway. Conclusion: HDAC6, a key modifier of T-cell receptor signaling, might represent a novel target for the treatment of CD8 T cellrelated skin diseases, including CHS and GVHD.

【 授权许可】

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