Immunomodulatory Functions of the NF-kB/IkB Family

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Abstract

This project aims to determine physiologically critical functions of NF-kappaB and IkappaB proteins in the context of specific biologic reactions. Research is based on the discovery of specific immunologic defects in mice rendered deficient for various NF-kappaB and IkappaB proteins. The ultimate goal is to identify critical molecular targets of the NF-kappaB factors in specific immune responses and to identify the essential signals that activate the factors. Previously we have generated mice deficient in the p52 subunit of NF-kappaB. The mutant mice are impaired in antibody responses to T-dependent antigens due to microarchitectural defects in secondary lymphoid organs. They lack B cell follicles and follicular dendritic cell (FDC) networks. Adoptive transfers now demonstrate that the major defect lies in stromal cells, presumably the FDC themselves. In contrast, certain deficiencies of the splenic marginal zone in these mutant mice are intrinsic to hematopoietic cells. Previously we also generated mice deficient in both p50 and p52 to uncover redundantly encoded functions of these highly homologous proteins. Significantly, these mice are blocked in the development of mature osteoclasts and of mature B cells. We further determined in adoptive transfer experiments that the block in generation of a mature B cell population is both intrinsic to B cells and cell autonomous. Immature B cells from bone marrow are still able to migrate to the spleen, but once there, they are no longer able to generate a longer-lived recirculating pool of mature B cells.