The class II Histone deacetylase 7 controls Interleukin 2 receptor expression and proliferation of primary cytotoxic T cells (84.8)

Abstract

Abstract Regulation of chromatin accessibility via class II histone deacetylases is a critical mechanism controlling gene expression. The paradigm for class II HDAC regulation is that in quiescent lymphocytes these molecules localise to the nucleus and form repressive complexes on chromatin. Antigen receptor activation of Protein Kinase D induces phosphorylation and nuclear export of HDACs thereby relieving their repressive actions on chromatin and gene expression. In this context, the present study has examined the regulation and function the class II histone deacetylase 7 in effector cytotoxic T cells (CTLs). This HDAC has been shown previously to function as a signal dependent repressor of gene transcription during T cell development in the thymus. We now show that HDAC7 is a critical regulator of Interleukin 2 receptor expression and proliferation in primary CTL. Strikingly, there is constitutive and sustained phosphorylation and export of HDAC7 from the nucleus to the cytosol in CTLs. The cytosolic localisation of HDAC7 is determined by the phosphorylation of key serine residues in the molecule S156, S322, S457 and by a balance of src kinase and diacylglycerol signalling pathways that increase its nuclear export and block its nuclear import. An HDAC7 mutant (S156A, S322A, S457A) that cannot be phosphorylated is thus maintained in the nucleus and prevents expression of the Interleukin2 (IL-2) receptor and accordingly inhibits CTL responses to IL-2. HDAC7 thus acts as a molecular switch to mediate IL-2 receptor expression and cellular responsiveness to IL-2 in primary T cells.