Deacetylase inhibitor trichostatin A down-regulates Foxp3 expression and reduces CD4+CD25+ regulatory T cells

The forkhead transcription factor Foxp3 is essential for the development and function of CD4+CD25+ regulatory T (Treg) cells, which act to maintain immune tolerance and prevent autoimmunity. Lysine acetylation that is regulated by lysine acetyltransferases and lysine deacetylases plays an important role in gene transcription and protein function. Lysine deacetylase inhibitor trichostatin A (TSA) is reported to up-regulate Foxp3 expression and increase the generation of CD4+CD25+ Treg cells in vivo. In contrast, we found that TSA dramatically reduced the levels of Foxp3 mRNA and protein in vitro. Moreover, TSA enhanced the activity of the Foxp3 promoter but increased the decay of Foxp3 mRNA. Furthermore, administration of TSA significantly impaired the expression of Foxp3 and reduced the number of CD4+CD25+Foxp3+ Treg cells in C57BL/6J mice. Thus, our results show that TSA reduces the expression of Foxp3 through induction of mRNA degradation in vitro. Accordingly, TSA decreases Foxp3 expression and reduces the number of Treg cells in vivo. Our results are not in agreement with previous reports, which are discussed.

Research highlights
► Lysine deacetylase inhibitor TSA markedly reduced the levels of Foxp3 mRNA and protein in vitro.
► TSA induced the degradation of Foxp3 mRNA in vitro.
► TSA impaired Foxp3 expression and reduces the number of CD4+CD25+Foxp3+ Treg cells in vivo.