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The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues.

Wu Q, Wang Y, Wang J, Hedgeman EO, Browning JL, Fu YX - J. Exp. Med. (1999)

Bottom Line: Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen.These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen.Taken together, these results support the notion that the signaling via LTbetaR by membrane LTalpha/beta is required for the presence of DCs in lymphoid tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA.

ABSTRACT
Although several cytokines, including tumor necrosis factor (TNF), can promote the growth of dendritic cells (DCs) in vitro, the cytokines that naturally regulate DC development and function in vivo have not been well defined. Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen. LTalpha(-/-) mice, lacking membrane LTalpha/beta and LTalpha(3), show markedly reduced numbers of DCs in the spleen. Unlike wild-type mice and TNF(-/-) mice that have densely clustered DCs in the T cell zone and around the marginal zone, splenic DCs in LTalpha(-/-) mice are randomly distributed. The reduced number of DCs in lymphoid tissues of LTalpha(-/-) mice is associated with an increased number of DCs in nonlymphoid tissues. The number of splenic DCs in LTalpha(-/-) mice is restored when additional LT-expressing cells are provided. Blocking membrane LTalpha/beta in wild-type mice markedly diminishes the accumulation of DCs in lymphoid tissues. These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen. Mice deficient in TNF receptor, which is the receptor for both soluble LTalpha(3) and TNF-alpha(3) trimers, have normal numbers of DCs. However, LTbetaR(-/-) mice show reduced numbers of DCs, similar to the mice lacking membrane LT alpha/beta. Taken together, these results support the notion that the signaling via LTbetaR by membrane LTalpha/beta is required for the presence of DCs in lymphoid tissues.

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Determination of DC number in mice deficient in LTα, TNF, or TNFR. Spleens from 6–10-wk-old wt (WT), TNF−/−, TNFR−/−, and LTα−/− mice were collected. (A) Splenocytes were stained for the DC marker (CD11c) and class II marker (I-Ab) as indicated. (B) The frozen spleen sections were stained for anti-CD11c antibody for DC (red) and anti-B220 antibody for B cells (brown). Data from one of five representative experiments is shown. (C) Both lymphoid and myeloid DC subsets are reduced in LTα−/− mice. The splenocytes were stained for DC subsets with CD11b/CD11c and CD11c/CD8α as indicated.
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Figure 1: Determination of DC number in mice deficient in LTα, TNF, or TNFR. Spleens from 6–10-wk-old wt (WT), TNF−/−, TNFR−/−, and LTα−/− mice were collected. (A) Splenocytes were stained for the DC marker (CD11c) and class II marker (I-Ab) as indicated. (B) The frozen spleen sections were stained for anti-CD11c antibody for DC (red) and anti-B220 antibody for B cells (brown). Data from one of five representative experiments is shown. (C) Both lymphoid and myeloid DC subsets are reduced in LTα−/− mice. The splenocytes were stained for DC subsets with CD11b/CD11c and CD11c/CD8α as indicated.

Mentions: TNF can promote the growth of DCs in vitro 1516. To assess the role of TNF in the development of DCs in vivo, splenocytes from TNF−/− and wt mice were stained for CD11c and MHC class II (I-Ab), and the number of DCs in the preparation was determined by flow cytometry. The total number of DCs in both types of mice was similar, suggesting that TNF is not essential for the development of DCs (Fig. 1 A and Table ). Interestingly, the number of DCs in LTα−/− mice was greatly reduced, especially for the CD11chighclass IIhigh subset (Fig. 1 A and Table ), suggesting a role for LTα in DC development. Soluble LTα and TNF-α are structurally related homotrimers (LTα3 and TNF-α3) that exhibit similar biological activities by binding to the defined TNFRs 1, so TNFR−/− mice were used to determine the role of TNFR in DC development (Fig. 1 and Table ). However, the normal number of DCs in the spleens of TNFR−/− mice suggests that signaling via TNFR by either LTα3 or TNF-α3 is not essential for the presence of DCs in the spleen.


The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues.

Wu Q, Wang Y, Wang J, Hedgeman EO, Browning JL, Fu YX - J. Exp. Med. (1999)

Determination of DC number in mice deficient in LTα, TNF, or TNFR. Spleens from 6–10-wk-old wt (WT), TNF−/−, TNFR−/−, and LTα−/− mice were collected. (A) Splenocytes were stained for the DC marker (CD11c) and class II marker (I-Ab) as indicated. (B) The frozen spleen sections were stained for anti-CD11c antibody for DC (red) and anti-B220 antibody for B cells (brown). Data from one of five representative experiments is shown. (C) Both lymphoid and myeloid DC subsets are reduced in LTα−/− mice. The splenocytes were stained for DC subsets with CD11b/CD11c and CD11c/CD8α as indicated.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195624&req=5

Figure 1: Determination of DC number in mice deficient in LTα, TNF, or TNFR. Spleens from 6–10-wk-old wt (WT), TNF−/−, TNFR−/−, and LTα−/− mice were collected. (A) Splenocytes were stained for the DC marker (CD11c) and class II marker (I-Ab) as indicated. (B) The frozen spleen sections were stained for anti-CD11c antibody for DC (red) and anti-B220 antibody for B cells (brown). Data from one of five representative experiments is shown. (C) Both lymphoid and myeloid DC subsets are reduced in LTα−/− mice. The splenocytes were stained for DC subsets with CD11b/CD11c and CD11c/CD8α as indicated.
Mentions: TNF can promote the growth of DCs in vitro 1516. To assess the role of TNF in the development of DCs in vivo, splenocytes from TNF−/− and wt mice were stained for CD11c and MHC class II (I-Ab), and the number of DCs in the preparation was determined by flow cytometry. The total number of DCs in both types of mice was similar, suggesting that TNF is not essential for the development of DCs (Fig. 1 A and Table ). Interestingly, the number of DCs in LTα−/− mice was greatly reduced, especially for the CD11chighclass IIhigh subset (Fig. 1 A and Table ), suggesting a role for LTα in DC development. Soluble LTα and TNF-α are structurally related homotrimers (LTα3 and TNF-α3) that exhibit similar biological activities by binding to the defined TNFRs 1, so TNFR−/− mice were used to determine the role of TNFR in DC development (Fig. 1 and Table ). However, the normal number of DCs in the spleens of TNFR−/− mice suggests that signaling via TNFR by either LTα3 or TNF-α3 is not essential for the presence of DCs in the spleen.

Bottom Line: Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen.These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen.Taken together, these results support the notion that the signaling via LTbetaR by membrane LTalpha/beta is required for the presence of DCs in lymphoid tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA.

ABSTRACT
Although several cytokines, including tumor necrosis factor (TNF), can promote the growth of dendritic cells (DCs) in vitro, the cytokines that naturally regulate DC development and function in vivo have not been well defined. Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen. LTalpha(-/-) mice, lacking membrane LTalpha/beta and LTalpha(3), show markedly reduced numbers of DCs in the spleen. Unlike wild-type mice and TNF(-/-) mice that have densely clustered DCs in the T cell zone and around the marginal zone, splenic DCs in LTalpha(-/-) mice are randomly distributed. The reduced number of DCs in lymphoid tissues of LTalpha(-/-) mice is associated with an increased number of DCs in nonlymphoid tissues. The number of splenic DCs in LTalpha(-/-) mice is restored when additional LT-expressing cells are provided. Blocking membrane LTalpha/beta in wild-type mice markedly diminishes the accumulation of DCs in lymphoid tissues. These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen. Mice deficient in TNF receptor, which is the receptor for both soluble LTalpha(3) and TNF-alpha(3) trimers, have normal numbers of DCs. However, LTbetaR(-/-) mice show reduced numbers of DCs, similar to the mice lacking membrane LT alpha/beta. Taken together, these results support the notion that the signaling via LTbetaR by membrane LTalpha/beta is required for the presence of DCs in lymphoid tissues.

Show MeSH
Related in: MedlinePlus