Intestinal mast cell progenitors require CD49d beta 7 (alpha A beta 7 integrin) for tissue-specific homing

Mast cells (MCs) are centrally important in allergic inflammation of the ai r-ways, as well as in the intestinal immune response to helminth infection. A single lineage of bone marrow (BM)-derived progenitors emigrates from th e circulation and matures into phenotypically distinct MCs in different tis sues. Because the mechanisms of MC progenitor (MCp) homing to peripheral ti ssues have not been evaluated, we used limiting dilution analysis to measur e the concentration of MCp in various tissues of mice deficient for candida te homing molecules. MCp were almost completely absent in the small intesti ne but were present in the lung, spleen, BM, and large intestine of beta7 i ntegrin-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 al phaE integrin (CD103), the beta2 integrin (CD18), or the recombination acti vating gene (RAG)-2 gene either alone or in combination with the interleuki n (IL)-receptor common gamma chain. Therefore, it is the alpha4 beta7 integ rin and not the alphaE beta7 integrin that is critical, and lymphocytes and natural killer cells play no role in directing MCp migration under basal c onditions. When MCp in BALB/c mice were eliminated with sublethal doses of gamma -radiation and then reconstituted with syngeneic BM, the administrati on of anti-alpha4 beta7 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 translo cate into the intestine. Inasmuch as MCp are preserved in the lungs of beta 7 integrin-deficient and anti-alpha4 beta7 integrin-treated mice but not in the small intestine, alpha4 beta7 integrin is critical for tissue specific extravasation for localization of MCp in the small intestine, but not the lungs.