Regulation of antigen presentation and antigen presenting cells
Work in our laboratory is focused on the molecular mechanisms that regulate the expression of Major Histocompatibility Complex class II (MHC-II) genes and the function of specialised antigen presenting cells (APCs) in humans and mice. MHC-II molecules are cell-surface proteins that are of central importance to the immune system because they present peptides to the antigen receptor of CD4+ helper T lymphocytes. MHC-II restricted antigen presentation by specialised APCs guides the development of CD4+ T cells in the thymus and instructs the function of these cells during the initiation, implementation and regulation of protective immune responses against pathogens and tumors. It is also pivotal for the maintenance of self-tolerance and the breakdown of tolerance in autoimmune diseases. Studying the molecular mechanisms that control MHC-II expression and the function of APCs thus represents an important contribution to molecular immunology and immunopathology. Four key transcription factors (RFXANK, RFX5, RFXAP and CIITA) that are both essential and dedicated for the activation of MHC-II genes have been identified by our study of a hereditary immunodeficiency disease called the Bare Lymphocyte Syndrome. Past work concentrated on the structure, function and expression of these transcription factors, and how they collaborate to activate the expression of MHC-II genes in health and during the course of disease. This work allowed us to generate valuable tools that are being used to study the role MHC-II expression by different APC subsets in vivo, particularly by thymic epithelial cells and different dendritic cell (DC) subtypes. More recently, we have extended these investigations to encompass the regulatory circuits that control the activation and function of DCs in response to individual and combined microbial and endogenous stimuli. We address these questions by using a combination of biochemical and cell-based in vitro approaches to address the basic transcriptional mechanisms in various human and mouse cell types, and the generation of transgenic and knockout mice to investigate the consequences of deregulated gene expression in vivo.