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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, lung, spleen, and BM of wild-type (C57BL/6, +/+, white bars) control and β7 integrin-deficient mice (−/−, black bars) evaluated in parallel. The data are from three separate experiments and the values are the mean ± SEM. SCF plus IL-3 was used to determine MCp concentration, expressed as the number of MCp/106 MNCs.
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fig2: Concentrations of MCp in the small intestine, lung, spleen, and BM of wild-type (C57BL/6, +/+, white bars) control and β7 integrin-deficient mice (−/−, black bars) evaluated in parallel. The data are from three separate experiments and the values are the mean ± SEM. SCF plus IL-3 was used to determine MCp concentration, expressed as the number of MCp/106 MNCs.

Mentions: Mice with various gene disruptions have been used to establish the role of various integrins, particularly β7 and β2 integrins, in the trafficking of T cells into the gut-associated lymphoid tissues (23, 29–31). We took advantage of such mice to investigate the role of αE, β7, and β2 integrins on MCp trafficking to the intestine and lung. The β7 integrin chain deficiency resulted in a virtual ablation of the MCp reservoir in the small intestine without a reduction in the lung, spleen, or BM MCp concentrations (Fig. 2) . MCp concentrations in the large intestine were similar in both strains as well (282 and 392 MCp/106 MNCs for BL/6 and β7 integrin-deficient mice, respectively, in a single analysis). The average concentration of MCp in the small intestines of β7 integrin-deficient mice was only 26 ± 22 MCp/106 MNCs (mean ± SEM, n = 3), whereas BL/6 mice analyzed in parallel had an average of 1,440 ± 770 MCp/106 MNCs. The β7 integrin chain is found associated with the α4 (CD49d) and the αE (CD103) integrin chains (23, 26, 29, 32). Unlike the deficiency in the β7 integrin chain, a deficiency in the αE integrin chain had no effect on intestinal MCp concentrations (Table II). Normal concentrations of MCp also were observed in the lung and BM of these animals. Normal concentrations of MCp were observed in the intestine and BM in both β2 integrin-deficient and ICAM-1–deficient mice as well (Table II). Thus, under basal conditions, intestinal MCp trafficking requires the α4β7 integrin but apparently not the αEβ7 or β2 integrins.


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, lung, spleen, and BM of wild-type (C57BL/6, +/+, white bars) control and β7 integrin-deficient mice (−/−, black bars) evaluated in parallel. The data are from three separate experiments and the values are the mean ± SEM. SCF plus IL-3 was used to determine MCp concentration, expressed as the number of MCp/106 MNCs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195984&req=5

fig2: Concentrations of MCp in the small intestine, lung, spleen, and BM of wild-type (C57BL/6, +/+, white bars) control and β7 integrin-deficient mice (−/−, black bars) evaluated in parallel. The data are from three separate experiments and the values are the mean ± SEM. SCF plus IL-3 was used to determine MCp concentration, expressed as the number of MCp/106 MNCs.
Mentions: Mice with various gene disruptions have been used to establish the role of various integrins, particularly β7 and β2 integrins, in the trafficking of T cells into the gut-associated lymphoid tissues (23, 29–31). We took advantage of such mice to investigate the role of αE, β7, and β2 integrins on MCp trafficking to the intestine and lung. The β7 integrin chain deficiency resulted in a virtual ablation of the MCp reservoir in the small intestine without a reduction in the lung, spleen, or BM MCp concentrations (Fig. 2) . MCp concentrations in the large intestine were similar in both strains as well (282 and 392 MCp/106 MNCs for BL/6 and β7 integrin-deficient mice, respectively, in a single analysis). The average concentration of MCp in the small intestines of β7 integrin-deficient mice was only 26 ± 22 MCp/106 MNCs (mean ± SEM, n = 3), whereas BL/6 mice analyzed in parallel had an average of 1,440 ± 770 MCp/106 MNCs. The β7 integrin chain is found associated with the α4 (CD49d) and the αE (CD103) integrin chains (23, 26, 29, 32). Unlike the deficiency in the β7 integrin chain, a deficiency in the αE integrin chain had no effect on intestinal MCp concentrations (Table II). Normal concentrations of MCp also were observed in the lung and BM of these animals. Normal concentrations of MCp were observed in the intestine and BM in both β2 integrin-deficient and ICAM-1–deficient mice as well (Table II). Thus, under basal conditions, intestinal MCp trafficking requires the α4β7 integrin but apparently not the αEβ7 or β2 integrins.

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