Non-canonical NF-κB drives a fate switch from germinal center to early effector B cells.

The non-canonical (NC) NF-κB pathway controls peripheral B-cell survival and follicular organization, pointing to a regulatory role during active adaptive immune responses. Here, we show that NC NF-κB activity is selectively attenuated in human germinal center B cells (GCBs), the population required to generate high-affinity antibodies, while remaining elevated in effector B cells. Accordingly, enforced NC NF-κB activation in murine B cells resulted in near-complete loss of GCB and high-affinity antibody production following immunization. These effects were primarily driven by NC NF-κB-induced reshaping of the immune microenvironment: activated B cells secreted IL-10, triggering premature expansion of regulatory T cells, limiting T cell help, and suppressing germinal center responses. Blocking IL-10 signaling was sufficient to normalize the niche and restore GCB. Concurrently, NC NF-κB activation promoted rapid B-cell differentiation into low-affinity antibody-secreting cells. Together, these findings identify NC NF-κB as a tunable rheostat linking B-cell signaling, immune-niche control, and humoral immunity.