MULTIFOCAL DEFECTS IN IMMUNE-RESPONSES IN RELB-DEFICIENT MICE

Mice with a targeted disruption of the Rel/nuclear factor-kappa B fami ly member RelB develop a complex inflammatory phenotype, myeloid hyper plasia, and splenomegaly due to extramedullary hemopoiesis. In this wo rk, we report that RelB-deficient mice, in addition to the pathologic changes, were highly susceptible to infection by the facultative intra cellular bacterium Listeria monocytogenes, RelB binds transcriptionall y active kappa B motifs in the TNF-alpha promoter in normal cells, and in vitro studies with macrophages isolated from RelB-deficient animal s revealed impaired production of TNF-alpha in response to LPS and IFN -gamma. RelB-deficient mice also were unable to mount a protective imm une response against lymphocytic choriomeningitis virus. These results indicate a defective T cell-macrophage interaction and cytotoxic T ce ll response, respectively, in mice lacking RelB. Analysis of resting a nd specific Ab production demonstrated that while RelB is not required for the secretion of Ig isotypes that result from heavy chain class s witching, it is necessary for normal production of Ag-specific IgC in response to T cell-dependent and -independent stimuli. Thus, RelB is n ot only essential for a normal hemopoietic system in the unchallenged animal, but also involved in various specific and nonspecific immune r esponses.