Mice Deficient in Nuclear Factor (NF)-κB/p52 Present with Defects in Humoral Responses, Germinal Center Reactions, and Splenic Microarchitecture

Abstract

p52 is a subunit of nuclear factor (NF)-κB transcription factors, most closely related to p50. Previously, we have shown that p52, but not p50 homodimers can form transactivating complexes when associated with Bcl-3, an unusual member of the IκB family. To determine nonredundant physiologic roles of p52, we generated mice deficient in p52. Null mutant mice were impaired in their ability to generate antibodies to T-dependent antigens, consistent with an absence of B cell follicles and follicular dendritic cell networks in secondary lymphoid organs, and an inability to form germinal centers. Furthermore, the splenic marginal zone was disrupted. These phenotypes are largely overlapping with those observed in Bcl-3 knockout animals, but distinct from those of p50 knockouts, supporting the notion of a physiologically relevant complex of p52 homodimers and Bcl-3. Adoptive transfer experiments further suggest that such a complex may be critical in accessory cell functions during antigen-specific immune reactions. Possible roles of p52 and Bcl-3 are discussed that may underlie the oncogenic potential of these proteins, as evidenced by recurrent chromosomal translocations of their genes in lymphoid tumors.

Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts

“…In the spleen of these mice, the perifollicular marginal zone, thought to be important for regulating cell migration during immune responses, is absent and the B-cell follicular areas are either absent or depleted. Although the failure of these mice to mount a normal T cell-dependent antibody response is associated with an inability to form germinal centers, this cannot simply be explained by intrinsic B-or T-cell defects, as nfkb2 7/7 lymphocytes exhibit only mildly impaired proliferative responses coupled with normal antibody or cytokine production when activation in culture (Franzoso et al, 1998). Instead, these immune de®ciencies appear to re¯ect a defect in antigen presentation by accessory cells.…”

“…However, unlike nfkb1, nfkb2 expression is restricted to the epithelium of the stomach and select areas of hemopoietic organs such as the thymic medulla, the marginal zone and periarterial sheath of the spleen (Attar et al, 1997). Mice lacking p52/p100 proteins develop normally, with the major defect being a disruption of splenic and lymph node architecture (CaamanÄ o et al, 1998;Franzoso et al, 1998). In the spleen of these mice, the perifollicular marginal zone, thought to be important for regulating cell migration during immune responses, is absent and the B-cell follicular areas are either absent or depleted.…”

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.…”

“…Mice deficient in the non-canonical pathway fail to segregate B-cell-T-cell zones and FDC networks, and they fail to form GCs following immunization. Marginal zone macrophages, which line the border between red and white pulp areas, are also absent or disorganized in RelB, p52, NIK or IKKa knockouts (Franzoso et al, 1998;Weih et al, 2001). Some splenic defects are also attributable to effects on hematopoietic cells.…”

“…Signaling through CD40 activates both canonical and non-canonical NF-kB pathways, although it is unclear which is operative in the response to T-dependent antigens. For example, whereas B cells from p52 À/À mice mount inadequate humoral responses to various T-dependent antigens, they exhibit a normal response following adoptive transfer into rag-1 À/À mice -indicating that this deficit is not intrinsic to B cells (Franzoso et al, 1998). Furthermore, B cells from relB À/À mice, although crippled in their proliferative response, undergo normal IgM secretion and class switching in response to various stimuli (Snapper et al, 1996a).…”