Using multiple human and mouse gene systems, our lab investigates genetic and epigenetic mechanisms that control immune system development, differentiation and gene expression. These are the fundamental processes that govern the ability of an immune cell, such as a lymphocyte to respond to an environmental threat, such as a virus or invading bacteria. In one gene system, we seek to determine how the major histocompatibility complex class II (MHC-II) genes are regulated. MHC-II proteins initiate adaptive immune responses by presenting antigens to T lymphocytes. We recently discovered that MHC-II genes are separated by genetic insulator elements that function to coordinate the expression of the entire locus by forming long-range interacting chromatin loops with each other and with the promoters of MHC-II genes. Intriguingly, when B lymphocytes differentiate to antibody producing plasma cells the novel regulatory loops and MHC-II gene expression is lost. We have initiated investigations into how B and T cells differentiate into effector cells following stimulation. These investigations focus on deriving the unique and underlying epigenetic inheritance patterns that are present within each cell type and how external stimuli (antigen) alter these programs. In another project, we are examining the regulation of the cell inhibitory factor programmed death-1 (PD-1). Expression and subsequent stimulation of the PD-1 cell surface receptor on T cells results in their functional exhaustion and inability to fight infection. Functional exhaustion of T cells occurs during chronic viral infections, such as that exemplified by HIV and in cancer. We have identified the key regulatory elements of PD-1 and found that PD-1 is epigenetically controlled by DNA methylation. For PD-1 the DNA methylation events are dynamic during the course of an acute but not chronic infection, suggesting that this pathway may be a target to prevent chronic viral infection. Through each of these studies, we hope to develop higher order and dynamic models of gene regulation and cell fate determination through which specific factors and pathways may be targeted for immune based therapies that can be used to treat infectious disease, autoimmunity, and cancer.