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Mature follicular dendritic cell networks depend on expression of lymphotoxin beta receptor by radioresistant stromal cells and of lymphotoxin beta and tumor necrosis factor by B cells.

Endres R, Alimzhanov MB, Plitz T, Fütterer A, Kosco-Vilbois MH, Nedospasov SA, Rajewsky K, Pfeffer K - J. Exp. Med. (1999)

Bottom Line: In contrast, the GC reaction was restored in LTbeta-/- hosts reconstituted with either wild-type or LTbetaR-/- BM.In BCR-/- recipients reconstituted with compound LTbeta-/-/BCR-/- or TNF-/-/BCR-/- BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent.Thus, development of splenic FDC networks depends on expression of LTbeta and TNF by B lymphocytes and LTbetaR by radioresistant stromal cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, D-81675 Munich, Germany.

ABSTRACT
The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that the cytokines tumor necrosis factor (TNF), lymphotoxin (LT) alpha, and LTbeta, as well as their receptors TNF receptor p55 (TNFRp55) and LTbetaR play essential roles in the development of GCs. To establish in which cell types expression of LTbetaR, LTbeta, and TNF is required for GC formation, LTbetaR-/-, LTbeta-/-, TNF-/-, B cell-deficient (BCR-/-), and wild-type mice were used to generate reciprocal or mixed bone marrow (BM) chimeric mice. GCs, herein defined as peanut agglutinin-binding (PNA+) clusters of centroblasts/centrocytes in association with follicular dendritic cell (FDC) networks, were not detectable in LTbetaR-/- hosts after transfer of wild-type BM. In contrast, the GC reaction was restored in LTbeta-/- hosts reconstituted with either wild-type or LTbetaR-/- BM. In BCR-/- recipients reconstituted with compound LTbeta-/-/BCR-/- or TNF-/-/BCR-/- BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent. Thus, development of splenic FDC networks depends on expression of LTbeta and TNF by B lymphocytes and LTbetaR by radioresistant stromal cells.

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Model of the molecular interactions essential for the establishment of splenic FDC networks associated with PNA+ cell clusters. B  cells provide the ligands LTα (references 28, 29), TNF, and LTβ required  for an effective engagement of the TNFRp55 (references 25, 26) and the  LTβR on specific radioresistant cells, which most likely represent FDC  precursors. In this cell population, both signaling pathways have to be  functional for mature splenic FDC networks to form. Note that the  present data do not elucidate whether signaling from the TNFRp55 and  the LTβR has to occur simultaneously or consecutively in the putative  FDC precursors. TNFRI, TNFRp55.
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Figure 4: Model of the molecular interactions essential for the establishment of splenic FDC networks associated with PNA+ cell clusters. B cells provide the ligands LTα (references 28, 29), TNF, and LTβ required for an effective engagement of the TNFRp55 (references 25, 26) and the LTβR on specific radioresistant cells, which most likely represent FDC precursors. In this cell population, both signaling pathways have to be functional for mature splenic FDC networks to form. Note that the present data do not elucidate whether signaling from the TNFRp55 and the LTβR has to occur simultaneously or consecutively in the putative FDC precursors. TNFRI, TNFRp55.

Mentions: Mice deficient for the TNFRp55 or the LTβR lack FDC networks and correctly localized PNA+ cell clusters, demonstrating the requirement of signals from these receptors for GC formation (20, 21). Development of PNA+ cell clusters and FDC networks in TNFRp55−/− mice is not rescued by transplantation of wild-type BM (25, 26), whereas TNFRp55−/− BM is as efficient as wild-type BM in reconstituting these structures in LTα−/− mice (26). These data indicate that for establishment of GCs, TNFRp55 is required on radioresistant stromal cells and not on radiosensitive BM-derived cells (25, 26). In the present study, LTβR−/− → LTβ−/−, LTβR−/− → B6, and B6 → LTβR−/− BM chimeric mice were used for the analysis of GC development, and evidence is provided that for formation of FDC networks expression of LTβR, like TNFRp55, is required on radioresistant cells, but not on BM-derived radiosensitive cells. Since FDCs are known to withstand high doses of irradiation (37), it is likely that putative FDC precursors are radioresistant cells that depend on signals from the TNFRp55 (25, 26) and the LTβR (this study) for differentiation to mature FDCs (Fig. 4). Alternatively, it is conceivable that radioresistant stromal cells different from FDC precursors exist that provide molecules needed for FDC maturation and depend on signals from the TNFRp55 and/or the LTβR in order to fulfill this function.


Mature follicular dendritic cell networks depend on expression of lymphotoxin beta receptor by radioresistant stromal cells and of lymphotoxin beta and tumor necrosis factor by B cells.

Endres R, Alimzhanov MB, Plitz T, Fütterer A, Kosco-Vilbois MH, Nedospasov SA, Rajewsky K, Pfeffer K - J. Exp. Med. (1999)

Model of the molecular interactions essential for the establishment of splenic FDC networks associated with PNA+ cell clusters. B  cells provide the ligands LTα (references 28, 29), TNF, and LTβ required  for an effective engagement of the TNFRp55 (references 25, 26) and the  LTβR on specific radioresistant cells, which most likely represent FDC  precursors. In this cell population, both signaling pathways have to be  functional for mature splenic FDC networks to form. Note that the  present data do not elucidate whether signaling from the TNFRp55 and  the LTβR has to occur simultaneously or consecutively in the putative  FDC precursors. TNFRI, TNFRp55.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: Model of the molecular interactions essential for the establishment of splenic FDC networks associated with PNA+ cell clusters. B cells provide the ligands LTα (references 28, 29), TNF, and LTβ required for an effective engagement of the TNFRp55 (references 25, 26) and the LTβR on specific radioresistant cells, which most likely represent FDC precursors. In this cell population, both signaling pathways have to be functional for mature splenic FDC networks to form. Note that the present data do not elucidate whether signaling from the TNFRp55 and the LTβR has to occur simultaneously or consecutively in the putative FDC precursors. TNFRI, TNFRp55.
Mentions: Mice deficient for the TNFRp55 or the LTβR lack FDC networks and correctly localized PNA+ cell clusters, demonstrating the requirement of signals from these receptors for GC formation (20, 21). Development of PNA+ cell clusters and FDC networks in TNFRp55−/− mice is not rescued by transplantation of wild-type BM (25, 26), whereas TNFRp55−/− BM is as efficient as wild-type BM in reconstituting these structures in LTα−/− mice (26). These data indicate that for establishment of GCs, TNFRp55 is required on radioresistant stromal cells and not on radiosensitive BM-derived cells (25, 26). In the present study, LTβR−/− → LTβ−/−, LTβR−/− → B6, and B6 → LTβR−/− BM chimeric mice were used for the analysis of GC development, and evidence is provided that for formation of FDC networks expression of LTβR, like TNFRp55, is required on radioresistant cells, but not on BM-derived radiosensitive cells. Since FDCs are known to withstand high doses of irradiation (37), it is likely that putative FDC precursors are radioresistant cells that depend on signals from the TNFRp55 (25, 26) and the LTβR (this study) for differentiation to mature FDCs (Fig. 4). Alternatively, it is conceivable that radioresistant stromal cells different from FDC precursors exist that provide molecules needed for FDC maturation and depend on signals from the TNFRp55 and/or the LTβR in order to fulfill this function.

Bottom Line: In contrast, the GC reaction was restored in LTbeta-/- hosts reconstituted with either wild-type or LTbetaR-/- BM.In BCR-/- recipients reconstituted with compound LTbeta-/-/BCR-/- or TNF-/-/BCR-/- BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent.Thus, development of splenic FDC networks depends on expression of LTbeta and TNF by B lymphocytes and LTbetaR by radioresistant stromal cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, D-81675 Munich, Germany.

ABSTRACT
The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that the cytokines tumor necrosis factor (TNF), lymphotoxin (LT) alpha, and LTbeta, as well as their receptors TNF receptor p55 (TNFRp55) and LTbetaR play essential roles in the development of GCs. To establish in which cell types expression of LTbetaR, LTbeta, and TNF is required for GC formation, LTbetaR-/-, LTbeta-/-, TNF-/-, B cell-deficient (BCR-/-), and wild-type mice were used to generate reciprocal or mixed bone marrow (BM) chimeric mice. GCs, herein defined as peanut agglutinin-binding (PNA+) clusters of centroblasts/centrocytes in association with follicular dendritic cell (FDC) networks, were not detectable in LTbetaR-/- hosts after transfer of wild-type BM. In contrast, the GC reaction was restored in LTbeta-/- hosts reconstituted with either wild-type or LTbetaR-/- BM. In BCR-/- recipients reconstituted with compound LTbeta-/-/BCR-/- or TNF-/-/BCR-/- BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent. Thus, development of splenic FDC networks depends on expression of LTbeta and TNF by B lymphocytes and LTbetaR by radioresistant stromal cells.

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