The broad purpose of this work is to further understand how microorganisms through their interaction with antigen presenting cells, such as macrophages and dendritic cells, affect the generation of T cell mediated immune responses via their ability to regulate the production of critical cytokines, such as IL-12 and IL-10. We initially studied the role of complement receptor 3 (CR3, CD11b/CD18) in regulation of IL-12 production from human monocytes. We determined that signaling via CR3, which serves as a receptor for a number of infectious organisms and endogenous molecules, such as the complement fragment opsonin iC3b, suppresses the ability of human monocytes to make IL-12 in response to known IL-12 stimuli. This effect was shown to occur in vitro in a dose-dependent fashion with a variety of CR3 ligands, such as antibodies to CR3 and iC3b-coated red blood cells, with a variety of IL-12 stimuli, including lipopolysaccharide (LPS), Staphlococcus aureus, Cowan strain 1 (SAC), and soluble CD40 ligand, and in vivo in a mouse model of septic shock following treatment with anti-CR3 antibodies. These studies established a novel role for CR3 in regulating cell mediated immune responses via its ability to regulate the production of IL-12, and suggest that organisms that bind to CR3 in either a complement-dependent or independent fashion have evolved to take advantage of this pathway to avoid the induction of IL-12 dependent T helper 1 (Th1) immune responses that are important for host defenses. Since these initial findings, we have focused our work on understanding the mechanism and relevance of CR3-mediated suppression of IL-12 production, and on how these findings relate to other newly defined signals for the regulation of IL-12 production in humans. These studies involve defining the relevant CR3- mediated intracellular signals and their effects on transcription factors that regulate IL-12 gene transcription, determining IL-12 production from cells of patients with a genetic defect in &#61538;2-integrin expression (leukocyte adhesion deficiency), and examining the role of CR3 activation on IL-12 production in vitro. Finally, the ability of antibodies to CR3, as well as CR4, to affect the outcome of ongoing Th1-mediated autoimmune diseases is being explored in a mouse model of inflammatory bowel disease.