The role of histone deacetylases in the control of T cell-mediated immunity
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators during development and differentiation by mediating dynamic changes in the acetylation of histones at lysine residues. In T cells, reversible changes in histone acetylation patterns have been shown to accompany many important processes ranging from VDJ recombination during T cell development to the induction of cytokine expression during Th1/Th2 effector differentiation. Further, in recent years many non-histone targets were identified and reversible lysine acetylation affects protein-protein and protein-DNA interactions, protein stability, enzymatic activity, intracellular localization and is also linked to metabolism. This demonstrates that lysine acetylation is an important post-translational modification likely to be comparable with protein phosphorylation. Eighteen HDACs have been identified in mammalian organisms, however dissecting individual roles for each member of the HDAC family in specific cell lineages and tissues remains a major scientific challenge. We are analyzing the role of HDAC1, HDAC2 and other members of the HDAC family in T cells and T cell-mediated immune diseases. These studies are performed in the framework of a special research program (SFB) “HDACs as regulators of T cell-mediated immunity in health and disease” , which is a newly established research network funded by the Austrian Science Fund (www.meduniwien.ac.at/HIT). The SFB is formed by an interdisciplinary consortium of eight research groups, of which seven are located in Vienna and one in Salzburg.
Molecular analysis of the zinc finger transcription factor MAZR
In our previous studies we identified that the BTB domain-containing zinc finger protein MAZR is an important transcriptional regulator of CD8 expression (Bilic et al., 2006, Nat Immunol) and further demonstrated that MAZR is part of the transcription factor network regulating CD4/CD8 cell fate choice of DP thymocytes (Sakaguchi et al., 2010, Nat Immunol; Sakaguchi et al., J Immunol, 2015). Using mice with a conditional deletion of MAZR in the T cell lineage we are focusing in ongoing studies on the further characterization of MAZR function in CD4+ and CD8+ T cells and in other cells of the hematopoietic system.
NCOR1 - a key regulator of Th cell differentiation
NCOR1 belongs to the important group of transcriptional cofactors that connects repressive chromatin-modifying enzymes with gene specific transcription factors. We previously demonstrated essential roles for NCOR1 during T cell development and in orchestrating transcriptional landscapes and effector function in peripheral CD4+ T cells. In ongoing studies we are addressing the role of NCOR1 in regulating T cell-mediated immunity in tissues.