Intestinal mast cell progenitors require CD49dbeta7 (alpha4beta7 integrin) for tissue-specific homing.
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.
Gurish
M F
MF
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. mgurish@rics.bwh.harvard.edu
Tao
H
H
Abonia
J P
JP
Arya
A
A
Friend
D S
DS
Parker
C M
CM
Austen
K F
KF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D018821:CD18 Antigens / Q000276:immunology; D002452:Cell Count; D002633:Chemotaxis / Q000276:immunology*; D016207:Cytokines / Q000008:administration & dosage / Q000276:immunology; D039001:Integrin alpha Chains; D039441:Integrin alpha4; D039641:Integrin beta Chains; D016023:Integrins / Q000235:genetics / Q000276:immunology*; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology; D019089:Stem Cell Factor / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D016207:Cytokines; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D016023:Integrins; D019089:Stem Cell Factor; C091367:alpha E integrins; C071777:integrin alpha4beta7; C091368:integrin beta7; D039441:Integrin alpha4; D019009:Proto-Oncogene Proteins c-kit