Coordination between NF-κB family members p50 and p52 is essential for mediating LTβR signals in the development and organization of secondary lymphoid tissues

Abstract

Recent studies revealed that the lymphotoxin/lymphotoxin beta receptor (LT)/ LT␤R system activates the noncanonical nuclear factor-B (NF-B) signaling pathway involving I kappa B kinase 1/I kappa B kinase ␣ (IKK1/IKK␣) and NF-B-inducing kinase (NIK) to direct processing of the nfb2 protein p100 to yield RelB:p52 complexes. Despite the biochemical evidence, LT-, RelB-, p52-deficient mice show discrepant phenotypes. We now demonstrate that p105/p50 also constitutes an important pathway for LT␤R signaling. Our studies revealed that mice deficient in either p50 or p52 have defects in the formation of inguinal lymph nodes (LNs), but that the complete defect in lymph node formation and splenic microarchitecture seen in LT-deficient mice is recapitulated only in mice deficient in both p50 and p52. Biochemically, we find not only that both p50-and p52-containing NF-B activities are induced by LT␤R signaling, but that the induction of NF-B-containing complexes by LT␤R engagement is perturbed in single knockouts. Importantly, the LT␤R can additionally activate the less well-characterized p52:RelA and p50:RelB pathways, which play pivotal roles in vivo for the development and organization of lymphoid structures. Our genetic, cellular, and molecular evidence points toward a model of LT-mediated NF-B regulation in which p105/p50 and p100/p52 have distinct and coordinating molecular specificities but differ in the upstream signaling pathways that regulate them. (Blood. 2006;107:1048-1055)

Crosstalk via the NF-κB signaling system

“…Lymph nodes are located throughout the body to monitor the draining fluids and migrating lymphocytes for pathological changes (Lo et al, 2006;Mebius, 2003). The ltbr -/-mice demonstrated that lymphotoxin-β receptor (LTβR) signaling critically regulates lymph node formation (Futterer et al, 1998;Rennert et al, 1998).…”

“…Analysis with radiation chimeras suggested a requirement for RelA within the nonhematopoietic stromal cells for the development of secondary lymphoid organs (Alcamo et al, 2002). Similarly, p50-deficient mice exhibited defects in lymphoid tissues with a loss of inguinal lymph nodes (Lo et al, 2006). A requirement of the RelA:p50 dimer in stromal cells for activating VCAM-1 or ICAM-1 gene expression during LTβR signaling (Dejardin et al, 2002;Lo et al, 2006) was proposed to be responsible for these lymph node phenotypes.…”

“…For example, nfkb2 -/-mice, which are deficient in the primary regulators of non-canonical NF-κB signaling p100/p52, display defects only in the inguinal lymph node formation with all other nodes present at wild type frequencies (Lo et al, 2006). It was proposed that the RelB:p50 dimer may be responsible for the incomplete penetrance of phenotype in nfkb2 -/-mice.…”

“…It was proposed that the RelB:p50 dimer may be responsible for the incomplete penetrance of phenotype in nfkb2 -/-mice. Indeed, nfkb1 -/-nfkb2 -/-double knockout mice displayed complete lack of lymph nodes, thus phenocopying LTβR deficient mice (Lo et al, 2006). Interestingly, nfkb1 -/-mice were also shown to have inguinal lymph node defects and derived MEF showed attenuated RelB activation in response to LTβR stimulation (Lo et al, 2006).…”

“…Indeed, nfkb1 -/-nfkb2 -/-double knockout mice displayed complete lack of lymph nodes, thus phenocopying LTβR deficient mice (Lo et al, 2006). Interestingly, nfkb1 -/-mice were also shown to have inguinal lymph node defects and derived MEF showed attenuated RelB activation in response to LTβR stimulation (Lo et al, 2006). As described earlier, rela -/-mice also exhibited an early organogenic defect with complete absence of lymph nodes in new born mice (Alcamo et al, 2002), and RelB:p52 dimer activation by LTβR signaling was shown to be defective in rela -/-MEF (Basak et al, 2008).…”