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A role for S1P and S1P1 in immature-B cell egress from mouse bone marrow.

Pereira JP, Xu Y, Cyster JG - PLoS ONE (2010)

Bottom Line: B lymphocyte egress from secondary lymphoid organs requires sphingosine-1-phosphate (S1P) and S1P receptor-1 (S1P1).Transgenic expression of S1P1 in developing B cells was sufficient to mobilize pro- and pre-B cells from the BM.We conclude that the S1P1-S1P pathway contributes to egress of immature-B cells from BM, and that this mechanism is partially redundant with other undefined pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America. Joao.Pereira@ucsf.edu

ABSTRACT
B lymphocyte egress from secondary lymphoid organs requires sphingosine-1-phosphate (S1P) and S1P receptor-1 (S1P1). However, whether S1P contributes to immature-B cell egress from the bone marrow (BM) has not been fully assessed. Here we report that in S1P- and S1P1-conditionally deficient mice, the number of immature-B cells in the BM parenchyma increased, while it decreased in the blood. Moreover, a slower rate of bromodeoxyuridine incorporation suggested immature-B cells spent longer in the BM of mice in which S1P1-S1P signaling was genetically or pharmacologically impaired. Transgenic expression of S1P1 in developing B cells was sufficient to mobilize pro- and pre-B cells from the BM. We conclude that the S1P1-S1P pathway contributes to egress of immature-B cells from BM, and that this mechanism is partially redundant with other undefined pathways.

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S1P1 surface expression in BM parenchymal and sinusoidal cells and impaired egress of immature-B cells from the BM of S1P-deficient mice.(A) S1P1 surface expression in BM parenchymal and sinusoidal naïve CD4+ T cells. Mice were treated with Ly5.2-PE antibodies intravenously for 2 minutes. T cells were gated as TCRβ+ CD4+ CD8− L-sel+, and further gated as parenchymal (Ly5.2−, black) and sinusoidal (Ly5.2+, gray). Top panel shows cells stained with a control rabbit antiserum, and bottom panel shows cell staining with an anti-S1P1 rabbit antiserum. Data are representative of two experiments (n = 6). (B) Number of developing B cell subsets in the BM parenchyma, sinusoids, blood and spleen of Sphk-1 and -2-deficient and littermate control mice. Data shown were pooled from 4 independent experiments. * P<0.05; ** P<0.005 (unpaired, two-tailed Student's t-test).
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pone-0009277-g003: S1P1 surface expression in BM parenchymal and sinusoidal cells and impaired egress of immature-B cells from the BM of S1P-deficient mice.(A) S1P1 surface expression in BM parenchymal and sinusoidal naïve CD4+ T cells. Mice were treated with Ly5.2-PE antibodies intravenously for 2 minutes. T cells were gated as TCRβ+ CD4+ CD8− L-sel+, and further gated as parenchymal (Ly5.2−, black) and sinusoidal (Ly5.2+, gray). Top panel shows cells stained with a control rabbit antiserum, and bottom panel shows cell staining with an anti-S1P1 rabbit antiserum. Data are representative of two experiments (n = 6). (B) Number of developing B cell subsets in the BM parenchyma, sinusoids, blood and spleen of Sphk-1 and -2-deficient and littermate control mice. Data shown were pooled from 4 independent experiments. * P<0.05; ** P<0.005 (unpaired, two-tailed Student's t-test).

Mentions: S1P1 is sensitive to down-modulation by ligand, and surface levels on CD4 T cells are high when cells are in low S1P environments and low when cells are in high S1P environments [4], [17]. Flow cytometric analysis of BM parenchymal and sinusoidal naïve CD4+ T cells showed detectable surface S1P1 on parenchymal cells compared to a lack of surface receptor on sinusoidal cells (Figure 3A) as recently reported [10], indicating that S1P concentrations are lower in the parenchyma than in sinusoids. Mice conditionally deficient in Sphk1 and Sphk2 (Sphk-deficient) showed normal numbers of developing B cells in BM, but their distribution was not assessed [4]. Thus, we revisited B cell development in Sphk-deficient mice, analyzing positioning of B cell subsets in BM by flow cytometry. We found a small but significant increase in the number of parenchymal immature IgDlo cells, and a reduction in their numbers within sinusoids (Figure 3). The number of immature IgDlo cells was approximately 2.6-fold lower in peripheral blood of S1P-deficient mice than in littermate controls. The accumulation in BM parenchyma and reduction in peripheral blood suggests that S1P also contributes to immature-B cell egress from BM (Figure 3).


A role for S1P and S1P1 in immature-B cell egress from mouse bone marrow.

Pereira JP, Xu Y, Cyster JG - PLoS ONE (2010)

S1P1 surface expression in BM parenchymal and sinusoidal cells and impaired egress of immature-B cells from the BM of S1P-deficient mice.(A) S1P1 surface expression in BM parenchymal and sinusoidal naïve CD4+ T cells. Mice were treated with Ly5.2-PE antibodies intravenously for 2 minutes. T cells were gated as TCRβ+ CD4+ CD8− L-sel+, and further gated as parenchymal (Ly5.2−, black) and sinusoidal (Ly5.2+, gray). Top panel shows cells stained with a control rabbit antiserum, and bottom panel shows cell staining with an anti-S1P1 rabbit antiserum. Data are representative of two experiments (n = 6). (B) Number of developing B cell subsets in the BM parenchyma, sinusoids, blood and spleen of Sphk-1 and -2-deficient and littermate control mice. Data shown were pooled from 4 independent experiments. * P<0.05; ** P<0.005 (unpaired, two-tailed Student's t-test).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2823786&req=5

pone-0009277-g003: S1P1 surface expression in BM parenchymal and sinusoidal cells and impaired egress of immature-B cells from the BM of S1P-deficient mice.(A) S1P1 surface expression in BM parenchymal and sinusoidal naïve CD4+ T cells. Mice were treated with Ly5.2-PE antibodies intravenously for 2 minutes. T cells were gated as TCRβ+ CD4+ CD8− L-sel+, and further gated as parenchymal (Ly5.2−, black) and sinusoidal (Ly5.2+, gray). Top panel shows cells stained with a control rabbit antiserum, and bottom panel shows cell staining with an anti-S1P1 rabbit antiserum. Data are representative of two experiments (n = 6). (B) Number of developing B cell subsets in the BM parenchyma, sinusoids, blood and spleen of Sphk-1 and -2-deficient and littermate control mice. Data shown were pooled from 4 independent experiments. * P<0.05; ** P<0.005 (unpaired, two-tailed Student's t-test).
Mentions: S1P1 is sensitive to down-modulation by ligand, and surface levels on CD4 T cells are high when cells are in low S1P environments and low when cells are in high S1P environments [4], [17]. Flow cytometric analysis of BM parenchymal and sinusoidal naïve CD4+ T cells showed detectable surface S1P1 on parenchymal cells compared to a lack of surface receptor on sinusoidal cells (Figure 3A) as recently reported [10], indicating that S1P concentrations are lower in the parenchyma than in sinusoids. Mice conditionally deficient in Sphk1 and Sphk2 (Sphk-deficient) showed normal numbers of developing B cells in BM, but their distribution was not assessed [4]. Thus, we revisited B cell development in Sphk-deficient mice, analyzing positioning of B cell subsets in BM by flow cytometry. We found a small but significant increase in the number of parenchymal immature IgDlo cells, and a reduction in their numbers within sinusoids (Figure 3). The number of immature IgDlo cells was approximately 2.6-fold lower in peripheral blood of S1P-deficient mice than in littermate controls. The accumulation in BM parenchyma and reduction in peripheral blood suggests that S1P also contributes to immature-B cell egress from BM (Figure 3).

Bottom Line: B lymphocyte egress from secondary lymphoid organs requires sphingosine-1-phosphate (S1P) and S1P receptor-1 (S1P1).Transgenic expression of S1P1 in developing B cells was sufficient to mobilize pro- and pre-B cells from the BM.We conclude that the S1P1-S1P pathway contributes to egress of immature-B cells from BM, and that this mechanism is partially redundant with other undefined pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America. Joao.Pereira@ucsf.edu

ABSTRACT
B lymphocyte egress from secondary lymphoid organs requires sphingosine-1-phosphate (S1P) and S1P receptor-1 (S1P1). However, whether S1P contributes to immature-B cell egress from the bone marrow (BM) has not been fully assessed. Here we report that in S1P- and S1P1-conditionally deficient mice, the number of immature-B cells in the BM parenchyma increased, while it decreased in the blood. Moreover, a slower rate of bromodeoxyuridine incorporation suggested immature-B cells spent longer in the BM of mice in which S1P1-S1P signaling was genetically or pharmacologically impaired. Transgenic expression of S1P1 in developing B cells was sufficient to mobilize pro- and pre-B cells from the BM. We conclude that the S1P1-S1P pathway contributes to egress of immature-B cells from BM, and that this mechanism is partially redundant with other undefined pathways.

Show MeSH