Abstract

Targeted disruption of the Rel/NF-B family members NF-B2, encoding p100/p52, and RelB in mice results in anatomical defects of secondary lymphoid tissues. Here, we report that development of Peyer's patch (PP)-organizing centers is impaired in both NF-B2- and RelB-deficient animals. IL-7-induced expression of lymphotoxin (LT) in intestinal cells, a crucial step in PP development, is not impaired in RelB-deficient embryos. LT receptor (LTR)-deficient mice also lack PPs, and we demonstrate that LTR signaling induces p52–RelB and classical p50–RelA heterodimers, while tumor necrosis factor (TNF) activates only RelA. LTR-induced binding of p52–RelB requires the degradation of the inhibitory p52 precursor, p100, which is mediated by the NF-B-inducing kinase (NIK) and the IB kinase (IKK) complex subunit IKK, but not IKK or IKK. Activation of RelA requires all three IKK subunits, but is independent of NIK. Finally, we show that TNF increases p100 levels, resulting in the specific inhibition of RelB DNA binding via the C-terminus of p100. Our data indicate an important role of p52–RelB heterodimers in lymphoid organ development downstream of LTR, NIK and IKK.