The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells.
Mast cell-mediated responses are likely to be regulated by the cross talk between activatory and inhibitory signals. We have screened human cord blood mast cells for recently characterized inhibitory receptors expressed on NK cells. We found that IRp60, an Ig superfamily member, is expressed on human mast cells. On NK cells, IRp60 cross-linking leads to the inhibition of cytotoxic activity vs target cells in vitro. IRp60 is constitutively expressed on mast cells but is down-regulated in vitro by the eosinophil proteins major basic protein and eosinophil-derived neurotoxin. An immune complex-mediated cross-linking of IRp60 led to inhibition of IgE-induced degranulation and stem cell factor-mediated survival via a mechanism involving tyrosine phosphorylation, phosphatase recruitment, and termination of cellular calcium influx. To evaluate the role of IRp60 in regulation of allergic responses in vivo, a murine model of allergic peritonitis was used in which the murine homolog of IRp60, LMIR1, was neutralized in BALB/c mice by mAbs. This neutralization led to a significantly augmented release of inflammatory mediators and eosinophilic infiltration. These data demonstrate a novel pathway for the regulation of human mast cell function and allergic responses, indicating IRp60 as a candidate target for future treatment of allergic and mast cell-associated diseases.
Bachelet
Ido
I
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Munitz
Ariel
A
Moretta
Alessandro
A
Moretta
Lorenzo
L
Levi-Schaffer
Francesca
F
D000818:Animals; D015703:Antigens, CD; D015550:Cell Degranulation; D002465:Cell Movement; D002470:Cell Survival; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D047093:Eosinophil Major Basic Protein / Q000494:pharmacology; D047208:Eosinophil-Derived Neurotoxin / Q000494:pharmacology; D004804:Eosinophils / Q000502:physiology; D005312:Fetal Blood; D006801:Humans; D007073:Immunoglobulin E / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008407:Mast Cells / Q000737:chemistry* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010538:Peritonitis / Q000139:chemically induced; D011971:Receptors, Immunologic / Q000032:analysis* / Q000235:genetics / Q000502:physiology*; D054340:Receptors, KIR
D015703:Antigens, CD; C515070:CD300A protein, human; D018836:Inflammation Mediators; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D007073:Immunoglobulin E; D010047:Ovalbumin; D047208:Eosinophil-Derived Neurotoxin; D047093:Eosinophil Major Basic Protein