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Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis.

Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, Ikuta K, Tamechika M, Yamaguchi K, Fukumoto T, Chiba T, Nishikawa SI - J. Exp. Med. (2001)

Bottom Line: The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC).Importantly, chemokines produced by VCAM-1(+)ICAM-1(+) nonlymphoid cells mediate the recruitment of lymphoid cells.Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Syogoin-Kawaharacho 53, Sakyo-ku, Kyoto 606-8507, Japan. khonda@virus.kyoto-u.ac.jp

ABSTRACT
Mice deficient in lymphotoxin beta receptor (LTbetaR) or interleukin 7 receptor alpha (IL-7Ralpha) lack Peyer's patches (PPs). Deficiency in CXC chemokine receptor 5 (CXCR5) also severely affects the development of PPs. A molecular network involving these three signaling pathways has been implicated in PP organogenesis, but it remains unclear how they are connected during this process. We have shown that PP organogenesis is initiated at sites containing IL-7Ralpha(+) lymphoid cells and vascular cell adhesion molecule (VCAM)-1/intercellular adhesion molecule (ICAM)-1 expressing nonlymphoid elements. Here we characterize these lymphoid and nonlymphoid components in terms of chemokine signals. The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC). Importantly, chemokines produced by VCAM-1(+)ICAM-1(+) nonlymphoid cells mediate the recruitment of lymphoid cells. Furthermore, we show that these VCAM-1(+)ICAM-1(+) cells are mesenchymal cells that are activated by lymphoid cells through the LTbetaR to express adhesion molecules and chemokines. Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.

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IL-7 induces LTα/β upregulation in PP inducers. (A–C) Histograms show LTβR-Ig staining in CD4+ cells. (A) CD4+ cells from E17.5 intestine after in utero treatment with A7R34 or control rat IgG at E15.5 were analyzed. inj., injected. (B) CD4+ cells from E15.5 intestine were analyzed after in vitro cultures in the absence or presence of rIL-7 at indicated amounts for 6 h. (C) Cells were preincubated with 3 μg/ml A7R34 or equal amounts of polyclonal rat IgG and then incubated with rIL-7 (40 U/ml) for 6 h. (D–G) E17.5 intestines after in utero treatment with either A7R34 or control rat IgG at E15.5 were analyzed. (D) Whole-mount in situ hybridization analysis of LTβ expression. Arrows indicate positive spots. (E) Whole-mount immunostaining with anti-CD4 mAb. Arrows indicate accumulation of CD4+ cells. (F) The number of CD4+CD3− cells in the intestine was measured by FACS®. (G) Chemotactic response of CD4+ cells from intestines after treatment with either control rat IgG (white bars) or A7R34 (black bars) to BLC or ELC.
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Figure 5: IL-7 induces LTα/β upregulation in PP inducers. (A–C) Histograms show LTβR-Ig staining in CD4+ cells. (A) CD4+ cells from E17.5 intestine after in utero treatment with A7R34 or control rat IgG at E15.5 were analyzed. inj., injected. (B) CD4+ cells from E15.5 intestine were analyzed after in vitro cultures in the absence or presence of rIL-7 at indicated amounts for 6 h. (C) Cells were preincubated with 3 μg/ml A7R34 or equal amounts of polyclonal rat IgG and then incubated with rIL-7 (40 U/ml) for 6 h. (D–G) E17.5 intestines after in utero treatment with either A7R34 or control rat IgG at E15.5 were analyzed. (D) Whole-mount in situ hybridization analysis of LTβ expression. Arrows indicate positive spots. (E) Whole-mount immunostaining with anti-CD4 mAb. Arrows indicate accumulation of CD4+ cells. (F) The number of CD4+CD3− cells in the intestine was measured by FACS®. (G) Chemotactic response of CD4+ cells from intestines after treatment with either control rat IgG (white bars) or A7R34 (black bars) to BLC or ELC.

Mentions: We have previously reported that PP inducers are an essential source of LTα/β for PP development, and suggested the role of IL-7Rα signal for its induction. Indeed, exposure of pregnant mice to A7R34 at E15.5 suppressed LT expression in CD4+ cells of the PP anlage (Fig. 5A and Fig. D). To test whether IL-7 directly induces LTα/β expression, CD4+ cells sorted from embryonic intestines were incubated in vitro with rIL-7. This stimulation with rIL-7 resulted in induction of LTα/β in a dose-dependent manner (Fig. 5 B). The induction was inhibited by preincubation of the cells with A7R34 (Fig. 5 C). It thus appears likely that V+I+ cells are induced by LTα/β on the surface of PP inducers that are expressed in response to IL-7Rα signals.


Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis.

Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, Ikuta K, Tamechika M, Yamaguchi K, Fukumoto T, Chiba T, Nishikawa SI - J. Exp. Med. (2001)

IL-7 induces LTα/β upregulation in PP inducers. (A–C) Histograms show LTβR-Ig staining in CD4+ cells. (A) CD4+ cells from E17.5 intestine after in utero treatment with A7R34 or control rat IgG at E15.5 were analyzed. inj., injected. (B) CD4+ cells from E15.5 intestine were analyzed after in vitro cultures in the absence or presence of rIL-7 at indicated amounts for 6 h. (C) Cells were preincubated with 3 μg/ml A7R34 or equal amounts of polyclonal rat IgG and then incubated with rIL-7 (40 U/ml) for 6 h. (D–G) E17.5 intestines after in utero treatment with either A7R34 or control rat IgG at E15.5 were analyzed. (D) Whole-mount in situ hybridization analysis of LTβ expression. Arrows indicate positive spots. (E) Whole-mount immunostaining with anti-CD4 mAb. Arrows indicate accumulation of CD4+ cells. (F) The number of CD4+CD3− cells in the intestine was measured by FACS®. (G) Chemotactic response of CD4+ cells from intestines after treatment with either control rat IgG (white bars) or A7R34 (black bars) to BLC or ELC.
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Related In: Results  -  Collection

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Figure 5: IL-7 induces LTα/β upregulation in PP inducers. (A–C) Histograms show LTβR-Ig staining in CD4+ cells. (A) CD4+ cells from E17.5 intestine after in utero treatment with A7R34 or control rat IgG at E15.5 were analyzed. inj., injected. (B) CD4+ cells from E15.5 intestine were analyzed after in vitro cultures in the absence or presence of rIL-7 at indicated amounts for 6 h. (C) Cells were preincubated with 3 μg/ml A7R34 or equal amounts of polyclonal rat IgG and then incubated with rIL-7 (40 U/ml) for 6 h. (D–G) E17.5 intestines after in utero treatment with either A7R34 or control rat IgG at E15.5 were analyzed. (D) Whole-mount in situ hybridization analysis of LTβ expression. Arrows indicate positive spots. (E) Whole-mount immunostaining with anti-CD4 mAb. Arrows indicate accumulation of CD4+ cells. (F) The number of CD4+CD3− cells in the intestine was measured by FACS®. (G) Chemotactic response of CD4+ cells from intestines after treatment with either control rat IgG (white bars) or A7R34 (black bars) to BLC or ELC.
Mentions: We have previously reported that PP inducers are an essential source of LTα/β for PP development, and suggested the role of IL-7Rα signal for its induction. Indeed, exposure of pregnant mice to A7R34 at E15.5 suppressed LT expression in CD4+ cells of the PP anlage (Fig. 5A and Fig. D). To test whether IL-7 directly induces LTα/β expression, CD4+ cells sorted from embryonic intestines were incubated in vitro with rIL-7. This stimulation with rIL-7 resulted in induction of LTα/β in a dose-dependent manner (Fig. 5 B). The induction was inhibited by preincubation of the cells with A7R34 (Fig. 5 C). It thus appears likely that V+I+ cells are induced by LTα/β on the surface of PP inducers that are expressed in response to IL-7Rα signals.

Bottom Line: The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC).Importantly, chemokines produced by VCAM-1(+)ICAM-1(+) nonlymphoid cells mediate the recruitment of lymphoid cells.Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Syogoin-Kawaharacho 53, Sakyo-ku, Kyoto 606-8507, Japan. khonda@virus.kyoto-u.ac.jp

ABSTRACT
Mice deficient in lymphotoxin beta receptor (LTbetaR) or interleukin 7 receptor alpha (IL-7Ralpha) lack Peyer's patches (PPs). Deficiency in CXC chemokine receptor 5 (CXCR5) also severely affects the development of PPs. A molecular network involving these three signaling pathways has been implicated in PP organogenesis, but it remains unclear how they are connected during this process. We have shown that PP organogenesis is initiated at sites containing IL-7Ralpha(+) lymphoid cells and vascular cell adhesion molecule (VCAM)-1/intercellular adhesion molecule (ICAM)-1 expressing nonlymphoid elements. Here we characterize these lymphoid and nonlymphoid components in terms of chemokine signals. The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC). Importantly, chemokines produced by VCAM-1(+)ICAM-1(+) nonlymphoid cells mediate the recruitment of lymphoid cells. Furthermore, we show that these VCAM-1(+)ICAM-1(+) cells are mesenchymal cells that are activated by lymphoid cells through the LTbetaR to express adhesion molecules and chemokines. Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.

Show MeSH
Related in: MedlinePlus