Regulation of late B cell differentiation by intrinsic IKKα-dependent signals

NF-κB-inducing kinase (NIK)-mediated IKKα phosphorylation activates the alternative NF-κB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-βR, BAFF-R, and CD40. Although NIK, IKKα, and p52 are all critical regulators of LT-βR 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-κB. Here we use mice bearing targeted mutations of the IKKα activation loop Ser(176/180) (IKKα(AA)) to address the B cell-intrinsic functions of NIK–IKKα signaling in vivo. We find that IKKα(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–IKKα–p52 axis is not as linear and exclusive as previous studies suggest, and IKKα possesses critical NF-κB-independent functions in B cells