How is tolerance induced to self-antigens that arise late in development or are inaccessible to the thymus and environmental antigens in the flora of the gut and airways? How are autoreactive T cells that escape negative selection, deleted or anergized in the periphery? This Program Project will address the central hypothesis that the immature DC functions to maintain peripheral tolerance, while the mature DC induces immunity. Four Projects will explore the mechanisms that underlie this ability of DCs to discriminate among infectious and self-antigens, potential defects in autoimmune states, and ways to manipulate these mechanisms to induce tolerance. In Project 1, Dr. Ralph Steinman will focus on the mechanisms by which DCs can induce tolerance to pancreatic islets. He will investigate maturation stimuli to selectively activate DCs in vivo and utilize this knowledge to induce peripheral tolerance to a surrogate beta cell antigen. Insulinoma cells will be studied to establish conditions for tolerizing the immune system to beta cell autoantigens, using the ability of DCs to cross-present islet cell autoantigens. In Project 2, Dr. Jeffrey Ravetch will focus on the specific role of immunoreceptors ITAM (an activation immunoreceptor) and ITIM (an inhibitory immunoreceptor) and signaling in DCs to induce maturation or maintain tolerance. The Fcgamma receptor (FcgammaR) system and its ligand, the immune complex, will be exploited to investigate how the balance between activation and inhibitory signaling can determine the in vivo outcome of antigens targeted to DCs. Through the use of novel genetically targeted animals, the role of the FcgammaR system in susceptibility to autoimmunity will be determined and manipulated to re-establish tolerance. In Project 3, Dr. Alexander Tarakhovsky will study the oncogene Src-family kinases in DC maturation and antigen presentation. Through the use of conditional disruptions in the negative regulators Csk and Cbp, he will determine the role of these pathways in DC function. To further define the signals involved in DC maturation, he proposes to study a novel toll-like receptor protein, RP105, expressed on DCs. In Project 4, Dr. Michel Nussenzweig will specifically target antigens to DCs in vivo to define their role in maintaining tolerance. Inducing DC maturation after targeting will be investigated as a way to convert a tolerogenic signal to an immunogenic signal. These approaches will be used in the experimental autoimmune encephalomyelitis (EAE) model to determine if targeting myelin oligodendrocyte glycoprotein (MOG) to DCs in various states of maturation can either induce tolerance or disease. Mice will be genetically engineered to express DCs arrested at the immature or mature state to test the hypothesis that the state of DC activation will determine if an antigenic stimulus is tolerogenic or immunogenic.
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