Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals.

NF-kappaB-inducing kinase (NIK)-mediated IKKalpha phosphorylation activates the alternative NF-kappaB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-betaR, BAFF-R, and CD40. Although NIK, IKKalpha, and p52 are all critical regulators of LT-betaR signaling in stromal cells during humoral immune responses, lymphocytes require NIK, but not p52, for optimal Ig production. This disparity suggests that NIK possesses critical cell-type-specific functions that do not depend on NF-kappaB. Here we use mice bearing targeted mutations of the IKKalpha activation loop Ser(176/180) (IKKalpha(AA)) to address the B cell-intrinsic functions of NIK-IKKalpha signaling in vivo. We find that IKKalpha(AA) B cells mount normal primary antibody responses but do not enter germinal centers. This defect likely derives from ineffective early T-B cell collaboration and leads to impaired generation of humoral memory and relatively short-lived, low-affinity antibody production. Our findings contrast with those obtained by using p52(-/-) B cells, which mount normal Ig responses, and alymphoplasia (NIK mutant) B cells, which produce very little primary Ig. Thus, the NIK-IKKalpha-p52 axis is not as linear and exclusive as previous studies suggest, and IKKalpha possesses critical NF-kappaB-independent functions in B cells.