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Intestinal mast cell progenitors require CD49dbeta7 (alpha4beta7 integrin) for tissue-specific homing.

Gurish MF, Tao H, Abonia JP, Arya A, Friend DS, Parker CM, Austen KF - J. Exp. Med. (2001)

Bottom Line: A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues.Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions.The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. mgurish@rics.bwh.harvard.edu

ABSTRACT
Mast cells (MCs) are centrally important in allergic inflammation of the airways, as well as in the intestinal immune response to helminth infection. A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues. Because the mechanisms of MC progenitor (MCp) homing to peripheral tissues have not been evaluated, we used limiting dilution analysis to measure the concentration of MCp in various tissues of mice deficient for candidate homing molecules. MCp were almost completely absent in the small intestine but were present in the lung, spleen, BM, and large intestine of beta7 integrin-deficient mice (on the C57BL/6 background), indicating that a beta7 integrin is critical for homing of these cells to the small intestine. MCp concentrations were not altered in the tissues of mice deficient in the alphaE integrin (CD103), the beta2 integrin (CD18), or the recombination activating gene (RAG)-2 gene either alone or in combination with the interleukin (IL)-receptor common gamma chain. Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions. When MCp in BALB/c mice were eliminated with sublethal doses of gamma-radiation and then reconstituted with syngeneic BM, the administration of anti-alpha4beta7 integrin, anti-alpha4 integrin, anti-beta7 integrin, or anti-MAdCAM-1 monoclonal antibodies (mAbs) blocked the recovery of MCp in the small intestine. The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine. Inasmuch as MCp are preserved in the lungs of beta7 integrin-deficient and anti-alpha4beta7 integrin-treated mice but not in the small intestine, alpha4beta7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.

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Concentrations of MCp in the small intestine and lung of C57BL/6 (white bars) and BALB/c (black bars) mice. MNCs were isolated from the intestine or the lung of normal C57BL/6J or BALB/c mice by enzymatic digestion. The MCp concentration is the number of MCp per 106 MNCs as determined by limiting dilution analysis with the cytokine combinations of SCF plus IL-3, IL-3 alone, or SCF plus IL-6 plus IL-10 (Triad). The values are the means ± SEM for five experiments. ND, not done.
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fig1: Concentrations of MCp in the small intestine and lung of C57BL/6 (white bars) and BALB/c (black bars) mice. MNCs were isolated from the intestine or the lung of normal C57BL/6J or BALB/c mice by enzymatic digestion. The MCp concentration is the number of MCp per 106 MNCs as determined by limiting dilution analysis with the cytokine combinations of SCF plus IL-3, IL-3 alone, or SCF plus IL-6 plus IL-10 (Triad). The values are the means ± SEM for five experiments. ND, not done.

Mentions: As an initial assessment of cytokines to be used for the optimal analysis of tissue MCp concentrations, we compared IL-3 alone, the cytokine triad of SCF plus IL-6 plus IL-10, and SCF plus IL-3. The cytokine triad is active on early Sca1+ stem cells and generates less mature cells, termed early metamastocytes, from BM than IL-3 alone (25), while SCF plus IL-3 is active on fetal blood promastocytes that do not respond to either cytokine alone (20). We determined the MCp concentration in the C57BL/6 (BL/6) and BALB/c mouse strains, which are the background strains of the various genetic mutants used in these studies. Similar concentrations of MCp were found in the intestine of both strains when the MNCs were cultured in either SCF plus IL-6 plus IL-10 or IL-3 alone (Fig. 1) . However, SCF plus IL-3 provided a significantly greater concentration of MCp from the intestine of BALB/c mice (P = 0.009), but not from BL/6 mice (P = 0.5), than that obtained with IL-3 or SCF plus IL-6 plus IL-10. The concentration of intestinal MCp detected with SCF plus IL-3 is about threefold greater than in BM of BALB/c mice (3,057 ± 757 versus 924 ± 155 MCp/106 MNCs, mean ± SEM, n = 5 and n = 6, respectively), but the two concentrations are equivalent in BL/6 mice (876 ± 223 versus 992 ± 57 MCp/106 MNCs, n = 5 and n = 2, respectively). None or very few colonies were detected in cultures containing SCF alone. In contrast to the large concentration of intestinal MCp, the concentration of MCp in the lung is 20–50-fold less in both mouse strains (Fig. 1, note different scale), although, again, the BALB/c mice show many more SCF plus IL-3 responsive progenitors in this tissue than does the BL/6 strain. The concentration of IL-3 responsive progenitors is comparable for the lung of both strains and similar to the concentration of SCF plus IL-3 responsive progenitors in the BL/6 strain. In the BALB/c mice, comparable concentrations of MCp are detectable with SCF plus IL-6 plus IL-10 or SCF plus IL-3 in the lung. As SCF plus IL-3 was optimal for the BALB/c strain and sufficient for the BL/6 strain, this combination was used for all subsequent assays of tissue MCp concentrations.


Intestinal mast cell progenitors require CD49dbeta7 (alpha4beta7 integrin) for tissue-specific homing.

Gurish MF, Tao H, Abonia JP, Arya A, Friend DS, Parker CM, Austen KF - J. Exp. Med. (2001)

Concentrations of MCp in the small intestine and lung of C57BL/6 (white bars) and BALB/c (black bars) mice. MNCs were isolated from the intestine or the lung of normal C57BL/6J or BALB/c mice by enzymatic digestion. The MCp concentration is the number of MCp per 106 MNCs as determined by limiting dilution analysis with the cytokine combinations of SCF plus IL-3, IL-3 alone, or SCF plus IL-6 plus IL-10 (Triad). The values are the means ± SEM for five experiments. ND, not done.
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Related In: Results  -  Collection

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fig1: Concentrations of MCp in the small intestine and lung of C57BL/6 (white bars) and BALB/c (black bars) mice. MNCs were isolated from the intestine or the lung of normal C57BL/6J or BALB/c mice by enzymatic digestion. The MCp concentration is the number of MCp per 106 MNCs as determined by limiting dilution analysis with the cytokine combinations of SCF plus IL-3, IL-3 alone, or SCF plus IL-6 plus IL-10 (Triad). The values are the means ± SEM for five experiments. ND, not done.
Mentions: As an initial assessment of cytokines to be used for the optimal analysis of tissue MCp concentrations, we compared IL-3 alone, the cytokine triad of SCF plus IL-6 plus IL-10, and SCF plus IL-3. The cytokine triad is active on early Sca1+ stem cells and generates less mature cells, termed early metamastocytes, from BM than IL-3 alone (25), while SCF plus IL-3 is active on fetal blood promastocytes that do not respond to either cytokine alone (20). We determined the MCp concentration in the C57BL/6 (BL/6) and BALB/c mouse strains, which are the background strains of the various genetic mutants used in these studies. Similar concentrations of MCp were found in the intestine of both strains when the MNCs were cultured in either SCF plus IL-6 plus IL-10 or IL-3 alone (Fig. 1) . However, SCF plus IL-3 provided a significantly greater concentration of MCp from the intestine of BALB/c mice (P = 0.009), but not from BL/6 mice (P = 0.5), than that obtained with IL-3 or SCF plus IL-6 plus IL-10. The concentration of intestinal MCp detected with SCF plus IL-3 is about threefold greater than in BM of BALB/c mice (3,057 ± 757 versus 924 ± 155 MCp/106 MNCs, mean ± SEM, n = 5 and n = 6, respectively), but the two concentrations are equivalent in BL/6 mice (876 ± 223 versus 992 ± 57 MCp/106 MNCs, n = 5 and n = 2, respectively). None or very few colonies were detected in cultures containing SCF alone. In contrast to the large concentration of intestinal MCp, the concentration of MCp in the lung is 20–50-fold less in both mouse strains (Fig. 1, note different scale), although, again, the BALB/c mice show many more SCF plus IL-3 responsive progenitors in this tissue than does the BL/6 strain. The concentration of IL-3 responsive progenitors is comparable for the lung of both strains and similar to the concentration of SCF plus IL-3 responsive progenitors in the BL/6 strain. In the BALB/c mice, comparable concentrations of MCp are detectable with SCF plus IL-6 plus IL-10 or SCF plus IL-3 in the lung. As SCF plus IL-3 was optimal for the BALB/c strain and sufficient for the BL/6 strain, this combination was used for all subsequent assays of tissue MCp concentrations.

Bottom Line: A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues.Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions.The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. mgurish@rics.bwh.harvard.edu

ABSTRACT
Mast cells (MCs) are centrally important in allergic inflammation of the airways, as well as in the intestinal immune response to helminth infection. A single lineage of bone marrow (BM)-derived progenitors emigrates from the circulation and matures into phenotypically distinct MCs in different tissues. Because the mechanisms of MC progenitor (MCp) homing to peripheral tissues have not been evaluated, we used limiting dilution analysis to measure the concentration of MCp in various tissues of mice deficient for candidate homing molecules. MCp were almost completely absent in the small intestine but were present in the lung, spleen, BM, and large intestine of beta7 integrin-deficient mice (on the C57BL/6 background), indicating that a beta7 integrin is critical for homing of these cells to the small intestine. MCp concentrations were not altered in the tissues of mice deficient in the alphaE integrin (CD103), the beta2 integrin (CD18), or the recombination activating gene (RAG)-2 gene either alone or in combination with the interleukin (IL)-receptor common gamma chain. Therefore, it is the alpha4beta7 integrin and not the alphaEbeta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal conditions. When MCp in BALB/c mice were eliminated with sublethal doses of gamma-radiation and then reconstituted with syngeneic BM, the administration of anti-alpha4beta7 integrin, anti-alpha4 integrin, anti-beta7 integrin, or anti-MAdCAM-1 monoclonal antibodies (mAbs) blocked the recovery of MCp in the small intestine. The blocking mAbs could be administered as late as 4 d after BM reconstitution with optimal inhibition, implying that the MCp must arise first in the BM, circulate in the vasculature, and then translocate into the intestine. Inasmuch as MCp are preserved in the lungs of beta7 integrin-deficient and anti-alpha4beta7 integrin-treated mice but not in the small intestine, alpha4beta7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.

Show MeSH
Related in: MedlinePlus