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. 1997 Jun 10;94(12):6319-23.
doi: 10.1073/pnas.94.12.6319.

Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor

M Pasparakis  1 , L Alexopoulou, M Grell, K Pfizenmaier, H Bluethmann, G Kollias
Affiliations

Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor

M Pasparakis et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A 1997 Aug 19;94(17):9510

Abstract

Targeted inactivation of genes in the tumor necrosis factor (TNF)/lymphotoxin (LT) ligand and receptor system has recently revealed essential roles for these molecules in lymphoid tissue development and organization. Lymphotoxin-alphabeta (LTalphabeta)/lymphotoxin-beta receptor (LTbeta-R) signaling is critical for the organogenesis of lymph nodes and Peyer's patches and for the structural compartmentalization of the splenic white pulp into distinct B and T cell areas and marginal zones. Moreover, an essential role has been demonstrated for TNF/p55 tumor necrosis factor receptor (p55TNF-R) signaling in the formation of splenic B lymphocyte follicles, follicular dendritic cell networks, and germinal centers. In contrast to a previously described essential role for the p55TNF-R in Peyer's patch organogenesis, we show in this report that Peyer's patches are present in both TNF and p55TNF-R knockout mice, demonstrating that these molecules are not essential for the organogenesis of this lymphoid organ. Furthermore, we show that in the absence of TNF/p55TNF-R signaling, lymphocytes segregate normally into T and B cell areas and a normal content and localization of dendritic cells is observed in both lymph nodes and Peyer's patches. However, although B cells are found to home normally within Peyer's patches and in the outer cortex area of lymph nodes, organized follicular structures and follicular dendritic cell networks fail to form. These results show that in contrast to LTalphabeta signaling, TNF signaling through the p55TNF-R is not essential for lymphoid organogenesis but rather for interactions that determine the cellular and structural organization of B cell follicles in all secondary lymphoid tissues.

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Figures

Figure 1
Figure 1
Defective follicular organization in Peyer’s patches of TNF and p55TNF-R knockout mice. Immunocytochemical analysis was performed on cryostat sections of Peyer’s patches from TNF and p55TNF-R knockout and wild-type control mice. Bound antibodies were visualized with diaminobenzidine and sections were counterstained with hematoxylin or methyl green. Peyer’s patches from wild-type mice stained with an antibody to IgM are found to contain organized B cell follicles (F) with visible germinal centers (GC). Large numbers of B cells are present in Peyer’s patches from TNF or p55TNF-R-deficient mice but they fail to form organized follicular structures and no germinal centers can be observed. Staining with the FDC-M2 mAb reveals the presence of FDC networks within follicles in Peyer’s patches from wild-type but not TNF or p55TNF-R-deficient mice. T cells stained here with an anti-CD3 mAb are found to form distinct T cell-rich areas. DC stained with the N418 anti-CD11c mAb are observed in the subepithelial region of Peyer’s patches from both TNF and p55TNF-R knockout mice. F, B cell follicles; GC, germinal centers; I, interfollicular regions; E, epithelium; L, lumen. (×25; ×125 for N418 staining).
Figure 2
Figure 2
Normal B cell homing, yet impaired formation of organized follicles in lymph nodes of mice lacking either TNF or the p55TNF-R. Cryostat sections of inguinal lymph nodes from wild-type, TNF knockout, and p55TNF-R knockout mice were analyzed by immunoperoxidase staining, developed with diaminobenzidine, and counterstained with hematoxylin. Staining with antibody to IgM shows a normal localization of B cells in the outer cortex of lymph nodes from TNF or p55TNF-R knockout mice (arrowheads); however, in contrast to wild-type mice, they are not organized into follicles but form a thin layer covering the cortex area. A similar distribution of B cells was observed by staining with anti-B220 or anti-IgD antibodies (not shown). FDC networks identified here with the FDC-M2 mAb are observed to form within follicles in wild-type but not in TNF- or p55-deficient lymph nodes. Additional staining with FDC-M1 failed to detect any FDC networks in lymph nodes from TNF or p55 knockout mice (not shown). In contrast, T cells visualized here with anti-CD3 mAb and N418+ DC (arrows) appear to develop normally in lymph nodes from these mice. Similar results were observed in mesenteric lymph nodes. F, B cell follicles; T, T cell-rich areas. (×20; ×100 for N418 staining).
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