HDAC1 restricts fungal-induced Th17 polarization to restrain tissue damage

Epigenetic mechanisms contribute to shaping many aspects of adaptive immunity, including T cell lineage functions in anti-infective surveillance. Histone deacetylases (HDAC) control T cell polarization but a role in fungal-specific T cell responses remains poorly understood. Here we show that CD4+ T cells are an integral part of the adaptive immune defense against invasive fungal infections. Temporally-resolved in vivo transcriptional profiles of splenic Th cells from infected mice harboring a CD4+-specific ablation of HDAC1 reveals its critical role in limiting T cell polarization towards Th17 at the expense of Th1-lineage commitment. Mechanistically, HDAC1 restricts expression of the cytokine receptors gp130 and TGFbRII on the T cell surface thus limiting Stat3 and Smad2/3 signaling in a fungal-specific manner. Controlled release of Th17-associated cytokines IL-17A and GM-CSF is vital to minimize epithelial apoptotic processes in renal tubular epithelial cells (RTECs) in vitro as well as during systemic infections in vivo. Consequently, protecting the host from excessive organ pathology, loss of kidney functionality and limiting fungal burdens, thus reducing sepsis-induced death during fungal infections. Collectively, this work shows that HDAC1 controls T cell lineage polarization, thus playing a critical role in the antifungal immune defense and infection outcome. Overall design: Mouse line with conditional deletion of HDAC1 in CD4 expressing T cells (HDAC1-cKO) or WT littermate controls were systemically infected with 1*10^4 C. albicans yeast cells per 21,5g body weight and total CD4+ T cells were magnetically sorted using negative selection from spleens 0, 4, 7 and 10 days after infection for RNAseq.