The role of HDAC1 and HDAC2 in CD4+ T cells

Reversible changes in histone acetylation patterns play a key role in the epigenetic regulation of gene expression. We previously showed that histone deacetylase (HDAC) 1 is a key regulator of Th2 cytokine responses. Interestingly, late T cell development in the absence of HDAC1 (using Cd4Cre) was not impaired. However, HDAC2 was up-regulated in the absence of HDAC1, thus we hypothesized compensatory functions between HDAC1 and HDAC2 in T cells. Indeed, by generating mice with a T cell-specific loss (Cd4Cre) of both HDAC1 and HDAC2, we obtained preliminary data showing that HDAC1/2 are essential to maintain CD4 lineage integrity by repressing a CD8 lineage effector program in CD4+ T cells. Based on these results, we propose to study how HDAC1/HDAC2 regulate T helper lineage integrity and function. Further, to fully understand how HDAC1/2 regulate CD4 lineage integrity, we will investigate on a genome-wide level the impact of HDAC1 and HDAC2 on the chromatin landscape and the transcriptional program in CD4+ T cells. Our study will provide important insight into fundamental aspects of how CD4 lineage integrity is maintained, into the immunoregulatory roles of HDAC1 and HDAC2, and into how T cell-mediated immune responses are linked with epigenetic gene regulatory networks.

The human immune system is based on a lively exchange of information between the cells, allowing for a coordinated response to germs or pathologically modified cells. This process requires the DNA information contained in the cells to be read and this is often regulated by so-called "epigenetic" processes (i.e. via the "degree of packaging" of the DNA). Special enzymes, the family of so-called histone deacetylases (HDACs), play an important role in this process. In total there are 18 different HDACs. They determine the "degree of packaging", that is to say how efficiently the information can be read. If the "degree of packaging" is lessened, it is easier to read the DNA, and this controls the expression of a large number of proteins. In addition to this, HDACs can also regulate the activity and function of proteins. This then leads to an increase in cell activity and boosts communication between the immune cells. In the immune system, increased cell activity during an immune response is primarily manifested by an increase in the number of special immune defense cells, T-cells (or T-lymphocytes). The extent of an immune response is thereby regulated by the HDAC family. In our FWF project we have shown that mice who have had HDAC1 switched off in the T-cells using a "molecular trick", do not develop experimental autoimmune encephalomyelitis (EAE), even when the disease is artificially provoked. EAE is an autoimmune disease which can be regarded as similar to MS in the animal model even though there are certain differences. Certain broad-spectrum HDAC molecule inhibitors are used in the treatment of patients with certain types of cancer. They are used to directly attack the tumor and in most cases the tumor shrinks. Many preclinical studies using an animal model suggest that HDAC inhibitors could also be effective in diseases of the immune system, like autoimmune diseases, but the potential therapeutic effects of broad-spectrum inhibitors are to some extent counterbalanced by serious side effects. Our study indicates that the development and use of HDAC1-specific inhibitors, with potentially fewer side-effects than broad-spectrum inhibitors, could be a possible approach for treating MS.