SFB-F70: HIT - HDACs as regulators of T cell-mediated immunity in health and disease

HDACs are key epigenetic and genetic regulators during development and cell differentiation. HDACs control the acetylation status of histones and non-histone proteins, thus modulating chromatin function and the activity of non-histone protein targets, respectively. Pan-HDAC inhibitors (HDACi) are clinically used for the treatment of certain cancers. Preclinical data indicate that HDAC modulation is beneficial for the therapy of T cell-mediated diseases, although the use of existing pan-HDACi for these indications is limited by their side effects. We hypothesize that the usage of subclass-specific and/or isoform-selective HDACi will avert limiting side effects and thereby broaden the clinical application spectrum of HDACi far beyond cancer. The overall aim of this 8-year SFB research program and consortium is to obtain an in-depth mechanistic understanding of HDAC function in T cells and to test essential regulatory roles of reversible lysine acetylation beyond histone modifications and epigenetic gene regulation in Th cells. With this we will be able to provide a mechanistic molecular rationale for the application of isoform-selective HDACi for the treatment of T cell-mediated diseases as well as to identify and characterize HDAC target genes and target proteins as novel drug targets.

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