This project is focused on the identification of physiologically critical functions of NF-kappaB transcription factors and their regulators, as well as the molecular mechanisms underlying these functions. NF-kappaB is a family of related dimeric transcription factors that serve as primary intracellular mediators of signals that are generated during innate and adaptive immune responses. In addition and importantly, dysregulation of NF-kappaB contributes significantly to inflammatory and autoimmune diseases as well as numerous tumors. It is thus imperative to understand the functions and mechanisms of action of NF-kappaB factors in both health and disease, as this will be required to devise appropriate strategies for therapeutic interventions aimed at curtailing dysregulated NF-kappaB in disease. To identify physiologic roles we make use of mouse models engineered to lack components of the NF-kappaB transcription factor family or their regulators. These mouse models are analyzed for defects in the immune system and are subjected to challenge with pathogens and experimentally induced diseases in order to educe critical roles of NF-kappaB components in maintaining health and in driving disease. Our work is primarily focused on alternatively activated NF-kappaB factors, a pathway of NF-kappaB activation that is initiated by a subset of TNF receptors, and it is focused on the atypical IkappaB family member Bcl-3, a regulator of NF-kappaB activity. Previously we have reported that alternatively activated NF-kappaB factors and Bcl-3 together are critical in the development of medullary thymic epithelial cells, which in turn are required for proper negative selection (elimination) of self-reactive T cells. In FY 2009 we have directly demonstrated that these NF-kappaB components acting in stromal cells in the thymus are required to efficiently eliminate specific self-reactive T cells;in the absence of these NF-kappaB components the self-reactive T cells escape into the periphery and initiate an auto-immune disease. Therefore, while loss of certain NF-kappaB components will impair the ability of immune cells to initiate inflammation, loss of other NF-kappaB components can induce inflammation through failure to enforce central tolerance. In FY 2009 we have discovered that the alternative pathway of activation initiated by the BAFF receptor is already contributing to early B cell development in the bone marrow;a mouse model in which classically and alternatively activated NF-kappaB complexes were partially ablated exhibited impaired development of immature B cells in the bone marrow. Previously we had shown that these NF-kappaB complexes were critical for full maturation of B cells in the spleen, a much later stage of B cell development. We further showed that the partial loss of NF-kappaB components at the early bone marrow stage of development resulted in increased apoptosis, consistent with a role for NF-kappaB in the survival of developing B lymphocytes. These data demonstrate important specific functions of Bcl-3 and the alternative pathway in the development of the immune system.