This project is focused on the identification of physiologically critical functions and mechanisms of action of NF-kB transcription factors and their regulators in health and disease. NF-kB is a family of related dimeric transcription factors that serve as primary intracellular mediators during innate and adaptive immune responses. In addition, and importantly, aberrant regulation of NF-kB plays a major role in inflammatory and autoimmune diseases as well as in numerous tumors. It is thus imperative to understand the functions and mechanisms of action of individual NF-kB factors and their regulators, as this will be required to devise appropriate strategies for therapeutic interventions aimed at curtailing aberrantly regulated NF-kB in a precisely targeted manner. To identify physiologic roles and mechanisms we make use of mouse models engineered to lack components of the NF-kB transcription factor family or their regulators, as well as models in which the NF-kB factors can be selectively activated. Our work is focused on alternatively and classically activated NF-kB factors, and especially on Bcl-3. The alternative NF-kB activation pathway is normally initiated by a subset of TNF receptors. Bcl-3 is an atypical IkB family member that functions as nuclear regulator of NF-kB activity. In the recent past we discovered a critical role for Bcl-3 in the ability of dendritic cells to properly prime T cells in culture to proliferate in response antigen. Priming of T cells by dendritic cells is crucial to initiate protective adaptive immune responses to pathogens, such as to Toxoplasma gondii, an intracellular pathogen that constitutes serious health risks in immune-compromised patients. Mice lacking Bcl-3 specifically in dendritic cells succumb to infection due to inadequately primed T cell responses. We also recently demonstrated that Bcl-3 has critical functions in keratinocytes to help delimit hypersensitivity reactions. Importantly we also discovered that Bcl-3 plays an important role in controlling the plasticity of effector T cells and, crucially, is required for the pathogenicity of auto-reactive T cells in the context of experimental autoimmune encephalomyelitis, a model for Multiple Sclerosis, and in the context of T cell transfer-induced colitis, a model for Inflammatory Bowel Disease. In FY 2016 we have explored critical cell-specific roles for Bcl-3 in a chronic inflammation-associated cancer model. We have determined that in contrast to Bcl-3s pro-tumorigenic role in B cells, Bcl-3 has a tumor suppressive role in gut epithelial cells in the colitis-associated azoxymethane/dextran sulfate sodium colon cancer model. We further found that this suppressive effect was mediated at least in part via Bcl-3s role in delimiting recruitment of myeloid-derived suppressor cells, cells known to protect tumorigenic cells. These findings illuminate the physiologic significance of Bcl-3 and the context-dependent manner in which is functions.
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