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Intestinal Mast Cell Progenitors Require CD49dß7 (4ß7 Integrin) for Tissue-specific Homing

¹ Department of Medicine, Harvard Medical School, Boston, MA 02115
² Department of Pathology, Harvard Medical School, Boston, MA 02115
³ Division of Rheumatology, Immunology and Allergy
⁴ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115

Address correspondence to Dr. M.F. Gurish, Smith Research Building, Room 616, One Jimmy Fund Way, Harvard Medical School, Boston, MA 02115. Phone: 617-525-1235; Fax: 617-525-1310; E-mail: mgurish{at}rics.bwh.harvard.edu

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 ß7 integrin-deficient mice (on the C57BL/6 background), indicating that a ß7 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 E integrin (CD103), the ß2 integrin (CD18), or the recombination activating gene (RAG)-2 gene either alone or in combination with the interleukin (IL)-receptor common chain. Therefore, it is the 4ß7 integrin and not the Eß7 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 -radiation and then reconstituted with syngeneic BM, the administration of anti-4ß7 integrin, anti-4 integrin, anti-ß7 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 ß7 integrin-deficient and anti-4ß7 integrin-treated mice but not in the small intestine, 4ß7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.

Key Words: E/CD103 integrin • ß2/CD18 integrin • c-kit • stem cell factor • MAdCAM-1

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