Functions and Mechanisms of NF-kB Factors and their Regulators

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

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 so-called alternatively, but also classically activated NF-kB, but especially on the regulators Bcl-3, and more recently also IkBzeta. The alternative NF-kB activation pathway is normally initiated by a subset of TNF receptors. Bcl-3 and IkBzeta are atypical IkB family member that function as nuclear regulators of NF-kB activity. We previously discovered a critical role for Bcl-3 in the ability of dendritic cells to properly prime T cells to proliferate in response antigen, and thus to initiate a protective adaptive immune response to pathogens, such as to Toxoplasma gondii, a serious health risk in immune-compromised patients. In the absence of Bcl-3 in dendritic cells, mice succumb to this infection. We also previously discovered that Bcl-3 has critical functions in keratinocytes to help delimit hypersensitivity reactions, and that Bcl-3 is required in T cells to become pathogenic in an autoimmune context, including in experimental autoimmune encephalomyelitis, a model for Multiple Sclerosis, and in T cell transfer-induced colitis, a model for Inflammatory Bowel Disease. In addition, we recently discovered that in contrast to its pro-tumorigenic role in B cells, it has a tumor-suppressive role in gut epithelial cells. Mice lacking Bcl-3 in these cells exhibited an increased tumor rate in a colitis inflammation-induced colon cancer model, highlighting the context-specific functions of the regulator. In FY2017 we have developed a number of tools and protocols to pursue our long-term goals. We generated a new mouse line that will allow us to uniquely label and track the Bcl-3 protein in primary cells. This tool will be invaluable to identify Bcl-3s target genes and its molecular mechanisms of action. In addition, we have generated a mouse line to allow for conditional ablation of the NF-kB regulator IkBzeta. This will greatly facilitate our investigations into the role of this regulator in inflammatory diseases and cancer. Furthermore, we have established a viral infection model that will allow us dissect the role of both NF-kB regulators in the development and differentiation of antigen-specific T cells in vivo. Finally, we have generated a mouse line in which the NF-kB subunit RelB can be conditionally eliminated. RelB is the target of the alternative NF-kB activation pathway, so this tool will permit us to explore the role of this pathway in inflammatory disease contexts, host defense and cancer.