Requirement for Nuclear Factor-κB Activation by a Distinct Subset of CD40-Mediated Effector Functions in B Lymphocytes

Abstract

CD40 stimulation, which is crucial for generating an effective T-dependent humoral response, leads to the activation of transcription factors NF-AT (nuclear factor of activated T cells), AP-1 (activator protein-1), and NF-κB (nuclear factor-κB). However, which CD40-mediated B cell functions actually require activation of specific transcription factors is unknown. We examined the causal relationship between NF-κB activation and CD40 effector functions by evaluating CD40 functions in the presence of an inducible mutant inhibitory κBα (IκBα) superrepressor. IκBαAA inhibited nuclear translocation of multiple NF-κB dimers without the complicating effect of depriving cells of NF-κB during development. This approach complements studies that use mice genetically deficient in single or multiple NF-κB subunits. Interestingly, only a subset of CD40 effector functions was found to require NF-κB activation. Both CD40-induced Ab secretion and B7-1 up-regulation were completely abrogated by expression of IκBαAA. Surprisingly, up-regulation of Fas, CD23, and ICAM-1 was partially independent, and up-regulation of LFA-1 was completely independent, of CD40-induced NF-κB activation. For the first time, it is clear that distinct transcription factors are required for the dynamic regulation of CD40 functions.