T cell activation requires a primary signal delivered by engagement of the T cell receptor (TCR) by MHC+ antigen complexes on antigen-presenting cells (APCs). In addition, a secondary signal delivered by the co-stimulatory molecules B7-1, B7-2 and CD40 on APCs, is also necessary for T cell activation. Amongst APCs, only dendritic cells (DCs) are thought to be capable of activating naive T lymphocytes. Microbial agents, such as lipopolysaccaride (LPS), are amongst the most important regulators of DC function. Engagement of Toll-like receptors (TLRs) by LPS and other microbial agents can lead to upregulation of cell surface expression of both MHC and co-stimulatory molecules on DCs, and the secretion of inflammatory cytokines. This process, often referred to as DC """"""""maturation"""""""", is thought to be essential for initiating productive T cell activation. While many recent studies have addressed mechanisms involved in controlling MHC cell surface expression in DCs, little is known about mechanisms involved in regulating co-stimulatory molecule (CM) surface expression in these cells. The goal of studies proposed here is to help understand this key aspect of immune regulation. To this end, we will investigate LPS-induced molecular mechanisms that eventually determine cell surface expression levels of the CMs B7-1, B7-2 and CD40 in DCs. A better understanding of these crucial mechanisms may provide insights for modulating expression of these molecules in therapeutic settings. An additional key goal of studies proposed here is to define molecular mechanisms involved in determining functional specificity of macrophage and DC-induced responses, in particular, those pertaining to regulation of CM expression.
The specific aims of this application are: (1) Transcriptional control of co-stimulatory molecule expression in DCs: role of NF-kB factors; (2) The role of post-transcriptional mechanisms in regulating co-stimulatory molecule cell surface expression in DCs; 3) Molecular mechanisms involved in determining functional specificity of macrophages and DCs: regulation of CM expression.
