One of the most important signals mediating lympho-organogenesis is the ligation ofLTpR on stromal cells by membrane-bound LTaiP2, expressed by hematopoieticcells. ActivationofLTpR triggers two NF-kB signaling pathways (Dejardin et al. 2002) (Fig. 3). The classic (canonical) NF-kB activity consists of the p50-RelA heterodimer (NF-kB1) and requires the inhibitor of kB kinase (IKK)y and IKKp subunits of the IKK complex (Weih and Caamano 2003). The alternative pathway involves phosphorylation of the precursor molecule p100 (subunit of NF-kB2) by the NF-KB-inducing kinase (NIK) and IKKa.
A mouse strain with a spontaneous, autosomal recessive single gene mutation, termed alymphoplasia (aly), was characterized by the absence of LNs and PPs, disorganized splenic and thymic architecture, and immunodeficiency (Miyawaki et al. 1994; Shinkura et al. 1996). The origin of the defect is a point mutation within NIK that retains catalytic activity (Shimizu et al. 1999). The precise function of NIK was uncovered by the generation of NIK-deficient mice (Yin et al. 2001). NIK is involved not only in the LTpR but also in the CD40, BAFF-R, and to some extent the toll-like receptor signaling cascade (Weih and Caamano 2003). Interestingly, aly/aly mice have normal expression levels of most adhesion molecules in the spleen and intestine, although MAdCAM-1+ cells are absent from the spleen (Koike et al. 1997). In addition, ligation of the LTpR was shown to induce a normal increase in VCAM-1 mRNA levels in aly/aly cells, although VCAM-1 protein levels were not induced (Dejardin et al. 2002; Matsumoto et al. 1999). Some homeostatic chemokines (CCL21) were normally expressed, whereas others were reduced or absent (CCL19, CXCL13) (Fagarasan et al. 2000). Therefore, the severe phe-notype of aly/aly mice may not exclusively rely on a defective LTpR-signaling in stromal cells. Supporting this idea, NIK was shown to be involved in the chemokine signaling pathway of hematopoietic cells, causing an intrinsic migratory defect of aly/aly lymphocytes (Fagarasan et al. 2000).
Studies in mice with mutations in individual Rel/NF-KB family members have demonstrated that both NF-kB1 and NF-kB2 signaling pathways are critical for PP and LN organogenesis and formation of lymphoid tissue architecture, although NF-KB1-deficient mice show a milder phenotype. RelB (NF-KB2-subunit)-deficient mice lack all LNs (Weih et al. 1995). PPs are barely detectable in RelB-/-, NF-kB2-/-, and IKKa-/- mice, whereas in NF-kB1-/-mice, LNs are normal, although PPs appear to be reduced in size and number (Matsushima et al. 2001; Paxian et al. 2002; Weih and Caamano 2003; Yilmaz et al. 2003). Weih and colleagues could show that the production of B cell follicle-forming chemokines such as CXCL13 by stromal cells was impaired in the absence of functional RelB (Weih et al. 2001). RelA (NF-KB1-subunit)-deletion is lethal in mice at E15 because of TNF receptor (TNFR)I-mediated apoptosis in hepatocytes. To circumvent this problem, Alcamo and colleagues have generated RelA-TNFRI-double-deficient mice. Whereas TNFRI-/- mice generate small PPs, RelA-/-TNFRI-/- mice completely lack peripheral and mucosal LNs and PPs because of a defect in stromal cells (Alcamo et al. 2002). Importantly, both RelA-/-TNFRI-/- mice and RelB-/- mice have normal numbers of lymphoid tissue inducer cells, indicating that functional NF-kB pathways are dispensable for the generation of the fetal hematopoietic cells but crucial for mesenchymal cell specification during LN and PP development.
NKX homeodomain proteins are members of the transcription factors implicated in controlling cell type specification, growth, and proliferation. A vertebrate member of the NK-2 class of homeobox genes is NKX2.3, found in midgut and hindgut mesoderm and spleen (Pabst et al. 1997). In mice, targeted deletion of the NKX2.3 gene leads to abnormal gut development, primarily in the distal part of the small intestine (Pabst et al. 1999). Depending on the genetic background, occasional asplenia was found in the NKX2.3-deficient mice. All mutant mice were shown to have morphological defects in the spleen and to lack marginal zones and expression of MAdCAM-1, a target gene of NKX2.3 transactivation, in secondary lymphoid organs (Pabst et al. 2000; Wang et al. 2000). The reduction of MAdCAM-1 expression was not a consequence of loss of FDCs, as normal numbers of FDC-M1+ cells could be detected in the white pulp (Wang et al. 2000). PPs were macroscopically absent, and only by histological analysis were small PPs with reduced follicle number occasionally found (Pabst et al. 2000; Wang et al. 2000). Segregation into T and B cell zones occurred normally in rudimentary PPs and in LNs except in mesenteric LNs, where T cells were abnormally found in the cortical area of the LN. Obviously, the complexity of the phenotype of mutant mice requires additional investigations to better understand the role of NKX2.3 for PP organogenesis and mesenteric LN organization.
The common y chain (yc) of the IL-2 family receptors (IL-2, IL-4, IL-7, IL-9, and IL-15) is linked to a Janus family tyrosine kinase JAK3. In IL-7Ra-, JAK3-, and yc-deficient mice, only mesenteric and occasionally brachial and axillary LNs were found, whereas inguinal, popliteal, sacral, and iliac LNs as well as PPs were undetectable. GCs were not found in secondary lymphoid organs (Adachi et al. 1998; Cao et al. 1995; Park et al. 1995). These data indicate that the IL-7R-signaling pathway is mandatory for PP and some LN organogenesis as well as GC formation (see also Sect. 4.2). Importantly, NALT development occurs independently of IL-7R, LT0R, and NIK signaling, providing evidence for a differential regulation of mucosal lymphoid tissue formation (Fukuyama et al. 2002).
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