Mast cell costimulation by CD226/CD112 (DNAM-1/Nectin-2): a novel interface in the allergic process.
Mast cells have critical effector functions in various immune reactions. In allergic inflammation, mast cells interact with tissue-infiltrating eosinophils, forming a regulatory unit in the late and chronic phases of the allergic process. However, the pathways and molecules within this unit are still largely undefined. Here, we show that human mast cells and eosinophils express DNAX accessory molecule 1 (DNAM-1, CD226) and its ligand Nectin-2 (CD112). CD226 synergizes with FcepsilonRI on mast cells, and its engagement augments degranulation through a pathway involving Fyn, linker of activation of T-cells, phospholipase C gamma2, and CD18. This pathway is subject to negative interference by inhibitory receptors and is completely inhibited by linking IgE with IRp60 (CD300a) using a bispecific antibody. Moreover, blocking CD112 expressed on eosinophils using neutralizing antibodies normalized the hyperactivity resulting from IgE-dependent activation of mast cells co-cultured with eosinophils. Our findings demonstrate a novel interface between these two effector cells, implicating relevance for in vivo allergic states. Moreover, costimulatory responses might be a critical component in allergic reactions and may therefore become novel targets for anti-allergic therapy.
Bachelet
Ido
I
Deparment of Pharmacology, The School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, and Department of Obstetrics and Gynecology, Hadassah University Hospital, Israel.
Munitz
Ariel
A
Mankutad
David
D
Levi-Schaffer
Francesca
F
D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D018821:CD18 Antigens / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D006967:Hypersensitivity; D007073:Immunoglobulin E / Q000737:chemistry; D053646:Interleukin-2 Receptor beta Subunit; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D015398:Signal Transduction; D000098862:T Lineage-Specific Activation Antigen 1
D000945:Antigens, Differentiation, T-Lymphocyte; D018821:CD18 Antigens; D000098862:T Lineage-Specific Activation Antigen 1; C508020:IL2RB protein, human; D053646:Interleukin-2 Receptor beta Subunit; D015375:Receptors, Interleukin-2; D007073:Immunoglobulin E; D051966:Phospholipase C gamma; D002118:Calcium