Requirement for nuclear factor-kappaB activation by a distinct subset of CD40-mediated effector functions in B...

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-kappaB (nuclear factor-kappaB). However, which CD40-mediated B cell functions actually require activation of specific transcription factors is unknown. We examined the causal relationship between NF-kappaB activation and CD40 effector functions by evaluating CD40 functions in the presence of an inducible mutant inhibitory kappaBalpha (IkappaBalpha) superrepressor. IkappaBalphaAA inhibited nuclear translocation of multiple NF-kappaB dimers without the complicating effect of depriving cells of NF-kappaB during development. This approach complements studies that use mice genetically deficient in single or multiple NF-kappaB subunits. Interestingly, only a subset of CD40 effector functions was found to require NF-kappaB activation. Both CD40-induced Ab secretion and B7-1 up-regulation were completely abrogated by expression of IkappaBalphaAA. 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-kappaB activation. For the first time, it is clear that distinct transcription factors are required for the dynamic regulation of CD40 functions.