Emory Vaccine Center
Professor and Chair
Department of Microbiology and Immunology, Emory University School of Medicine
My research centers on the global issue of how immune responses are regulated. I have chosen to approach this problem by focusing on the regulation of gene expression in two systems: the regulation of the human major histocompatibility complex class II genes (MHC class II) and the mechanisms by which tumor necrosis factor (TNF) regulates expression of a wide variety of genes.
The MHC class II genes are a family of genes that encode cell surface glycoproteins that function by presenting processed antigenic peptides to helper T cells. This function is responsible for initiating immune responses to foreign substances and results in the selective control of T cells and the production of specific antibodies. MHC class II products are expressed predominantly on B cells and antigen presenting cells, such as the macrophage. Experiments in the laboratory focus on identifying the role that chromatin plays in controlling gene expression. We use both in vitro and animal model knock-in/out systems to address the regulatory events that occur. One new area of investigation centers on the cell fate differentiation step between B cells and plasma cells. At this step global gene repressors and activators function to reprogram gene expression profiles. Our lab is using the master regulator CIITA as a model gene to study at this interface.
The regulation of genes by TNF marks the initiation of inflammatory responses. TNF controls a wide variety of genes that appear to be regulated by different mechanisms. We have chosen two genes that are regulated by TNF to study, the monocyte chemoattractant protein-1 gene (MCP-1) and the manganous superoxide dismutase gene. For each of these genes, we have identified complex TNF responsive regulatory elements, and for MCP-1 we have found a novel control of chromatin assembly of transcription factors that is mediated by TNF. Experiments are focused on examining this mechanism of control. Additionally, the factors that interact with the MCP-1 regulatory DNA appear to assemble as a multi component complex. Experiments are designed to determine the parameters of this complex both in vitro and in vivo.
Our research uses genetic, biochemical, and molecular biological technologies to unravel the mechanisms by which immune system genes are regulated. Two systems are studied. The first focuses on the major histocompatibility complex class II (MHC-II) genes, which are responsible for the presentation of foreign antigens to T lymphocytes. Proper tissue specific regulation of MHC-II genes is essential for the control and development of immune-based responses to pathogens and protecting from cancer and autoimmune disorders. Our studies examine the role that modifiers of chromatin structure play in organizing the architecture and expression of MHC-II genes. Recently, we found that interactions between transcriptional insulators and gene promoters form a unique architecture within the nucleus of each cell that is critical to expression of the gene system. Identification of the factors that control this architecture is a current thrust of the work as these are potential targets to manipulate immune responses and improve the efficacy of vaccination protocols. This repression of function creates a cell fate program, in which cells that can recognize the virus are unable to act to remove it. Recent work has shown that PD-1 is regulated by a complex set of transcription factors that activate or repress the expression of the gene depending on how the immune cells are exposed to antigen. We have also found that this cell fate program is regulated in an epigenetic manner such that the information gained during by one cell can be passed on to its descendants. This work has led to the development of technologies to dissect epigenetic processes across the genome and is being used to define cell differentiation programs. By understanding the mechanisms that govern regulation of these genes, reagents may ultimately be designed to combat chronic conditions.