Role of HDAC1 in T cell exhaustion during chronic infection

Cytotoxic T cells are an important component of our immune system, and play a central role during anti-viral and anti-tumor immune responses. Upon viral infection or tumor emergence cytotoxic T cells expand rapidly and exert cytolytic (i.e. cell killing) function to eliminate infected cells or tumors. However, when infections become chronic or tumors grow progressively, cytotoxic T cells display gradual loss of functionality and poor memory responses, widely known as T cell exhaustion. While T cell exhaustion limits pathology induced by immune responses, it impairs cytolytic function of the cells, leading to the exacerbation of the diseases. Therefore, understanding of the molecular/cellular mechanisms underlying T cell exhaustion is an important topic in immunology and highly relevant for clinical researches in chronic infections, tumors and autoimmune diseases. In this FWF project, we plan to elucidate the role of histone deacetylase 1 (HDAC1) for T cell exhaustion. HDAC1 mediates the deacetylation of histones and thereby regulates gene expression during various biological processes. By using a mouse model of chronic viral infection, we will comprehensively analyze the impact of HDAC1 deletion on T cell exhaustion, including viral titers and virus-induced immunopathology. Moreover, we will utilize state-of-the-art techniques, such as single cell RNA sequencing and ATAC-seq assay (Assay for Transposase-Accessible Chromatin using sequencing), and thereby aim to reveal molecular mechanisms by which HDAC1 controls T cell exhaustion. We anticipate that our project will provide novel insight into molecular/cellular mechanisms governing T cell exhaustion and thereby contribute to the better understanding of our immune system. Moreover, since a variety of HDAC inhibitors are currently under clinical investigation, the knowledge obtained from our study could be translated into more precise interpretation of such clinical trials and innovative approaches against viral infections and tumors.