Development of immunoglobulin k-chain-positive B cells, but not editing of immunoglobulin j-chain, depends on NF-jB signals A R T I C L E S

Abstract

By genetically ablating IjB kinase (IKK)-mediated activation of the transcription factor NF-jB in the B cell lineage and by analyzing a mouse mutant in which immunoglobulin k-chain-positive B cells are generated in the absence of rearrangements in the locus encoding immunoglobulin j-chain, we define here two distinct, consecutive phases of early B cell development that differ in their dependence on IKK-mediated NF-jB signaling. During the first phase, in which NF-jB signaling is dispensable, predominantly j-chain-positive B cells are generated, which undergo efficient receptor editing. In the second phase, predominantly k-chain-positive B cells are generated whose development is ontogenetically timed to occur after rearrangements of the locus encoding j-chain. This second phase of development is dependent on NF-jB signals, which can be substituted by transgenic expression of the prosurvival factor Bcl-2. It is well established that the NF-kB family of transcription factors is critical to B cell physiology 1,2 . Activation of NF-kB by the alternative pathway, which is mediated by NF-kB-inducing kinase and the inhibitor of NF-kB kinase 1 (IKK1; A001170) downstream of interactions between B cell-activation factor of the tumor necrosis factor family (BAFF) and BAFF-receptor, is essential for mature B cell survival 3 . In addition, mature B cells depend on continuous signaling through the canonical NF-kB pathway, in which activation of the IKK complex, which consists of IKK1, IKK2 (A001172) and NF-kB essential modulator (NEMO; A001628), is central 1 . In contrast, the function of NF-kB signaling in B cell development remains unclear 1 and is indeed highly controversial. Initial experiments addressed that issue in mice lacking one or two individual NF-kB transcription factors. Whereas the generation of mature B cells is generally impaired in most of these mutant mice, the effects are often mild in B cell progenitors and it has remained unresolved whether these defects are B cell autonomous 2 . Notably, genetic ablation of the BAFF-receptor or IKK1 seems not to affect B cell development in the bone marrow, at least in terms of proportions of cells at the various developmental stages 1,3 ; the same is true for ablation of the canonical pathway by knockout of IKK2 or NEMO specifically in B cell