Nuclear Factor (NF)-κB2 (p100/p52) Is Required for Normal Splenic Microarchitecture and B Cell–mediated Immune Responses

Abstract

The nfkb2 gene is a member of the Rel/NF-κB family of transcription factors. COOH-terminal deletions and rearrangements of this gene have been associated with the development of human cutaneous T cell lymphomas, chronic lymphocytic leukemias, and multiple myelomas. To further investigate the function of NF-κB2, we have generated mutant mice carrying a germline mutation of the nfkb2 gene by homologous recombination. NF-κB2–deficient mice showed a marked reduction in the B cell compartment in spleen, bone marrow, and lymph nodes. Moreover, spleen and lymph nodes of mutant mice presented an altered architecture, characterized by diffuse, irregular B cell areas and the absence of discrete perifollicular marginal and mantle zones; the formation of secondary germinal centers in spleen was also impaired. Proliferation of NF-κB2–deficient B cells was moderately reduced in response to lipopolysaccharide, anti-IgD-dextran, and CD40, but maturation and immunoglobulin switching were normal. However, nfkb2 (−/−) animals presented a deficient immunological response to T cell–dependent and –independent antigens. These findings indicate an important role of NF-κB2 in the maintenance of the peripheral B cell population, humoral responses, and normal spleen architecture.

NF-κB and the immune response

“…p52/RelB, which is activated downstream of NIK and IKKa, is thought to be the primary transcriptional mediator of several key organogenic factors including CXCL12, CXCL13, CCL19, CCL21 and MadCAM-1 (Yilmaz et al, 2003). The p52 single knockout lacks normal B-cell follicles, germinal centers (GCs) and Peyer's patch development (Caamano et al, 1998;Franzoso et al, 1998;Paxian et al, 2002); RelB is likewise also required for Peyer's patch development (Yilmaz et al, 2003). Although LN development occurs in RelB knockout mice, the nodes are small at birth and are resorbed perinatally.…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…RelA defi ciency in mice causes embryonic lethality due to extensive apoptosis in the liver (Beg et al, 1995). Mice lacking p50, p52, c-Rel or RelB respectively, are immunodefi cient, but develop normally to adulthood (Kontgen et al, 1995;Weih et al, 1995;Caamano et al, 1998) (Fig. 3).…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…An absence of p52/p100 is compatible with embryonic development and adult viability, but nfkb2 À/À mice display a range of immune defects that include a failure to develop normal secondary lymphoid structures, impaired B-lymphocyte maturation and abnormal T-cell function (Beinke and Ley, 2004). nfkb2 À/À mice exhibit disruption of splenic and lymph node architecture that includes an absence of the splenic perifollicular marginal zone and a marked depletion of B-cell follicular areas (Caamano et al, 1998;Franzoso et al, 1998). Similar defects are also present in mice lacking lymphotoxinb (LTb), lymphotoxin b-receptor (LTbR), NF-kB-inducing kinase (NIK) or RelB (Beinke and Ley, 2004).…”