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 pro-tolerogenic 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. HDAC5^–/– Tregs show increased acetylation of Foxo1, which is deacetylated by HDAC5 and important for maintaining the Treg cell phenotype. To test if this attenuated Treg formation and suppressive function translated into improved anti-cancer immunity, we inoculated HDAC5^–/– mice and littermate controls with a lung adenocarcinoma cell line. Cumulatively, lack of HDAC5 did not lead to better anti-cancer 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. This article is protected by copyright. All rights reserved.

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