Disrupted splenic architecture, but normal lymph node development in mice expressing a soluble lymphotoxin-beta receptor-IgG1 fusion protein - PubMed (original) (raw)

Disrupted splenic architecture, but normal lymph node development in mice expressing a soluble lymphotoxin-beta receptor-IgG1 fusion protein

R Ettinger et al. Proc Natl Acad Sci U S A. 1996.

Abstract

Early in ontogeny, the secondary lymphoid organs become populated with numerous cells of mesodermal origin which forms both the lymphoid and stromal elements. The critical receptor/ligand interactions necessary for lymphoid organogenesis to occur are for the most part unknown. Although lymphotoxin-alpha (LT alpha) has been shown to be required for normal lymph node, Peyer's patch, and splenic development, it is unclear if soluble LT alpha 3, and/or cell-bound lymphotoxin-alpha beta (LT alpha beta) mediate these developmental events. Here we report that blocking LT alpha beta/lymphotoxin-beta receptor (LT beta R) interaction in vivo by generating mice which express a soluble LT beta R-Fc fusion protein driven by the human cytomegalovirus promoter results in an array of anatomic abnormalities affecting both the spleen and Peyer's patches, but not the lymph nodes. These results demonstrate that surface LT alpha beta ligand plays a critical role in normal lymphoid organ development.

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Figures

Figure 1

Figure 1

Reduced size of spleen and Peyer’s patches in mice expressing a soluble LTβR–Fc transgene. Three- to 15-week-old mice expressing high levels of LTβR–Fc transgene product in the sera (0.5–6.5 μg/ml) from two separate founder lines were weighed and sacrificed, and the weight of the thymi and spleens was determined. Small intestine Peyer’s patches were counted, and the serosal surface area was determined. The percent control was determined by directly comparing sex-matched nontransgenic littermates to transgene-positive mice. Horizontal lines represent the group averages, and the mean ± the SD are as follows: body weight, 91% ± 11.0 (40 mice from 10 separate litters); spleen weight, 75% ± 15.7 (35 mice from 9 separate litters); thymus weight, 103% ± 35.2 (34 mice from 8 separate litters); and Peyer’s patch area, 39% ± 23.9 (23 mice from 6 separate litters).

Figure 2

Figure 2

Normal architecture of lymph nodes and Peyer’s patches from LTβR–Fc-expressing mice. Tissue sections of lymph node (A_–_D) and Peyer’s patch (E and F) from either low-expressing (A, C, and E), or high-expressing (B, D, and_F_) 6-week-old female LTβR–Fc transgenic mice (1610.2 and 1610.20 from Table 1). Tissue sections were stained with either hematoxylin/eosin (A and B,E and F) (×200), or with antibodies specific for T-cell (anti-CD4, red) and B-cell (anti-B220, green) antigens (C and D) (×100). Yellow staining indicates colocalization of both T and B cells. F, P, and GC indicate the location of the B-cell-rich follicles, the T-cell-rich paracortex, and the germinal centers, respectively.

Figure 3

Figure 3

Blockade of LTαβ/LTβR interactions results in abnormal splenic architecture. Splenic tissue sections from mice expressing either low (A, C, and_E_) or high (B, D, and_F_) levels of the LTβR–Fc transgene, as described in Fig. 2. Formalin-fixed sections were stained with hematoxylin/eosin (A_–_D). A single arrow represents the location of the central arterioles, and a double arrow defines the marginal zones. Frozen tissue sections were stained with antibodies specific for T-cell (red) and B-cell (green) antigens (E and F), as described in Fig. 2. (A,B, E, and F, ×100;C and D, ×400.)

Figure 4

Figure 4

Absence of splenic marginal zones in mice expressing a soluble LTβR–Fc chimeric fusion protein. Frozen tissue sections of spleen from 10-week-old female mice expressing high levels of the LTβR–Fc protein (2.5 μg/ml, from founder 201) (B, D, and F) or transgenic-negative mice (A, C, and_E_) were stained with antibodies specific for reticular fibroblasts with ER-TR7 (A and B), marginal zone macrophages with ER-TR9 (C and_D_), or marginal zone metallophilic macrophages with MOMA-1 (E and F), as described. A single arrow represents the location of the central arterioles, and a double arrow defines the marginal zones. F, P, RP, and rps shows the location of the B-cell-rich follicles, the T-cell-rich PALS, the red pulp, and the red pulp sinus, respectively. (×125.)

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