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

NF-kappa B-inducing kinase (NIK)-mediated IKK alpha phosphorylation activates the alternative INF-kappa B pathway, which is characterized by nuclear trainslocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-beta R, BAFF-R, and CD40. Although NIK, IKK alpha, and p52 are all critical regulators of LT-beta R 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-kappa B. Here we use mice bearing targeted mutations of the IKK alpha activation loop Ser(176/1180) (IKK alpha(AA)) to address the B cell-intrinsic functions of NIK-IKK alpha signaling in vivo. We find that IKK alpha(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 (INIK mutant) B cells, which produce very little primary Ig. Thus, the NIK-IKK alpha-pU axis is not as linear and exclusive as previous studies suggest, and IKK alpha possesses critical NIF-kappa B-inclependent functions in B cells.