title: HDAC5 controls the functions of Foxp3(+) T-regulatory and CD8(+) T cells.
abstract: Histone/protein deacetylases (HDACs) are frequently upregulated in human malignancies and have therefore become therapeutic targets in cancer therapy. However, inhibiting certain HDAC isoforms can have protolerogenic effects on the immune system, which could make it easier for tumor cells to evade the host immune system. Therefore, a better understanding of how each HDAC isoform affects immune biology is needed to develop targeted cancer therapy. Here, we studied the immune phenotype of HDAC5(-/-) mice on a C57BL/6 background. While HDAC5(-/-) mice replicate at expected Mendelian ratios and do not develop overt autoimmune disease, their T-regulatory (Treg) cells show reduced suppressive function in vitro and in vivo. Likewise, CD4(+) T-cells lacking HDAC5 convert poorly to Tregs under appropriately polarizing conditions. To test if this attenuated Treg formation and suppressive function translated into improved anticancer immunity, we inoculated HDAC5(-/-) mice and littermate controls with a lung adenocarcinoma cell line. Cumulatively, lack of HDAC5 did not lead to better anticancer immunity. We found that CD8(+) T cells missing HDAC5 had a reduced ability to produce the cytokine, IFN-γ, in vitro and in vivo, which may offset the benefit of weakened Treg function and formation. Taken together, targeting HDAC5 weakens suppressive function and de-novo induction of Tregs, but also reduces the ability of CD8(+) T cells to produce IFN-γ.
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Division of Transplant Immunology and Biesecker Center for Pediatric Liver Disease, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Shaun
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Kheng
authors.initials: K
authors.lastname: Newick
authors.affiliation: Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Liang-Chuan S
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Eva
authors.initials: E
authors.lastname: Falkensammer
authors.affiliation: Division of Transplant Immunology and Biesecker Center for Pediatric Liver Disease, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Transplant Immunology and Biesecker Center for Pediatric Liver Disease, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Rongxiang
authors.initials: R
authors.lastname: Han
authors.affiliation: Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, Düsseldorf, Germany.
authors.forename: Finn K
authors.initials: FK
authors.lastname: Hansen
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität Düsseldorf, Universitätsstr. 1, Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
authors.affiliation: Division of Transplant Immunology and Biesecker Center for Pediatric Liver Disease, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Beier
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D018390:Gene Targeting; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007371:Interferon-gamma; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: Foxp3; HDAC; Treg; cancer immunotherapy; lung adenocarcinoma