Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T‐regulatory cell function posttransplantation

• Published in: American journal of transplantation Vol. 18; no. 7; pp. 1596 - 1603
• Main Authors: Wang, L., Beier, U. H., Akimova, T., Dahiya, S., Han, R., Samanta, A., Levine, M. H., Hancock, W. W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.07.2018
• Subjects: Acetylation; Animals; basic (laboratory) research/science; cellular biology; Data processing; Deacetylation; Dephosphorylation; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression Regulation; Graft Survival - immunology; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Histones; Humans; immunobiology; immunosuppressant ‐ other; immunosuppression/immune modulation; Lymphocytes T; Lysine; Nonhistone proteins; Organ Transplantation; Phosphorylation; Protein Isoforms; T cell biology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; tolerance; translational research/science; Ubiquitination; translational research/science; immunosuppressant - other; immunosuppression/immune modulation; T cell biology; cellular biology; immunobiology; tolerance; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/ajt.14749

T‐regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini‐review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg‐dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform‐selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients. Biochemical and molecular studies show that the functions of Foxp3+ regulatory T cells can be pharmacologically enhanced with isoform‐specific histone/protein deacetylase inhibitors, providing real‐world options for sustained therapy in transplant recipients.