Abstract
Reversible lysine acetylation plays an important role in the regulation of T cell responses. HDAC1 has been shown to control peripheral T helper cells, however the role of HDAC1 in CD8+ T cell function remains elusive. By using conditional gene targeting approaches, we show that LckCre-mediated deletion of HDAC1 led to reduced numbers of thymocytes as well as peripheral T cells, and to an increased fraction of CD8+CD4– cells within the CD3/TCRβlo population, indicating that HDAC1 is essential for the efficient progression of immature CD8+CD4– cells to the DP stage. Moreover, CD44hi effector CD8+ T cells were enhanced in mice with a T cell-specific deletion of HDAC1 under homeostatic conditions and HDAC1-deficient CD44hi CD8+ T cells produced more IFNγ upon ex vivo PMA/ionomycin stimulation in comparison to wild-type cells. Naïve (CD44l°CD62L+) HDAC1-null CD8+ T cells displayed a normal proliferative response, produced similar amounts of IL-2 and TNFα, slightly enhanced amounts of IFNγ, and their in vivo cytotoxicity was normal in the absence of HDAC1. However, T cell-specific loss of HDAC1 led to a reduced anti-viral CD8+ T cell response upon LCMV infection and impaired expansion of virus-specific CD8+ T cells. Taken together, our data indicate that HDAC1 is required for the efficient generation of thymocytes and peripheral T cells, for proper CD8+ T cell homeostasis and for an efficient in vivo expansion and activation of CD8+ T cells in response to LCMV infection.
Highlights
Dynamic changes in histone acetylation patterns are mediated by the activity of histone acetyltransfereases (HATs) and histone deacetylases (HDACs) and are key events in the epigenetic regulation of gene expression
Our data indicate that HDAC1 is required for the efficient generation of thymocytes and peripheral T cells, for proper CD8+ T cell homeostasis and for an efficient in vivo expansion and activation of CD8+ T cells in response to lymphocyte choriomeningitis virus (LCMV) infection
Homeostatic analysis of CD8+ T cells in Hdac1f/fCd4Cre mice We previously reported that there are no major alterations during T cell development or in the composition of peripheral T cell subsets in Hdac1f/fCd4Cre mice [16]
Summary
Dynamic changes in histone acetylation patterns are mediated by the activity of histone acetyltransfereases (HATs) and histone deacetylases (HDACs) and are key events in the epigenetic regulation of gene expression. Many non-histone targets of HATs/HDACs have been described and it has been demonstrated that reversible lysine acetylation can affect proteinprotein and protein-DNA interactions, protein stability and intracellular localization. This implies that lysine acetylation is an important post-translational modification regulating a variety of cellular pathways and broadening the functional role of HATs/HDACs beyond epigenetic gene regulation [1]. Loss of HDAC1 (using the Cd4Cre delete strain) led to an increased inflammatory response in an in vivo allergic airway inflammation model and mice with HDAC1-deficient T cells displayed an increase in all clinical parameters of this Th2-type asthma model. This study clearly demonstrated an important function for HDAC1 in peripheral T helper cells, the role of HDAC1 in CD8+ T cells as well as during earlier steps of T cell development has not been explored
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