Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors.
Histone deacetylase inhibitors are under investigation in the clinic as a new class of anti-cancer therapeutics. While recent studies have also suggested their potential as inhibitors of a wide spectrum of inflammatory reactions, the anti-inflammatory mechanism of action of these compounds is not fully defined. We show here that the histone deacetylase inhibitors MS-275 and SAHA induce the generation of regulatory T cells (Tregs) from anti-CD3/anti-CD28-stimulated human CD4(+)CD25(-) T cells. These Tregs express the regulatory T cell-associated transcription factor Foxp3 and display suppressive activity against CD4(+)CD25(-) T cell proliferation. Topical treatment with histone deacetylase inhibitors also induces Foxp3 expression in the draining lymph nodes and the skin in the context of a murine contact hypersensitivity model. These findings suggest that Treg generation may serve as a novel mechanism by which histone deacetylase inhibitors regulate the immune response, and provide an additional rationale for the use of histone deacetylase inhibitors in the treatment of inflammation.
Lucas
Julie L
JL
Bayer HealthCare Pharmaceuticals, Richmond, CA 94701, USA.
Mirshahpanah
Parham
P
Haas-Stapleton
Eric
E
Asadullah
Khusru
K
Zollner
Thomas M
TM
Numerof
Robert P
RP
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology; D004139:Dinitrofluorobenzene / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D000077337:Vorinostat
D001549:Benzamides; D018106:CD28 Antigens; D017252:CD3 Complex; D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; D000077337:Vorinostat; D004139:Dinitrofluorobenzene