title: Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5-induced eosinophil development.
abstract: Eosinophilia is a hallmark characteristic of T helper type 2 (TH2) cell-associated diseases and is critically regulated by the central eosinophil growth factor interleukin 5 (IL-5). Here we demonstrate that IL-5 activity in eosinophils was regulated by paired immunoglobulin-like receptors PIR-A and PIR-B. Upon self-recognition of β₂-microglobulin (β₂M) molecules, PIR-B served as a permissive checkpoint for IL-5-induced development of eosinophils by suppressing the proapoptotic activities of PIR-A, which were mediated by the Grb2-Erk-Bim pathway. PIR-B-deficient bone marrow eosinophils underwent compartmentalized apoptosis, resulting in decreased blood eosinophilia in naive mice and in mice challenged with IL-5. Subsequently, Pirb(-/-) mice displayed impaired aeroallergen-induced lung eosinophilia and induction of lung TH2 cell responses. Collectively, these data uncover an intrinsic, self-limiting pathway regulating IL-5-induced expansion of eosinophils, which has broad implications for eosinophil-associated diseases.
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, 69978, Israel.
authors.forename: Netali
authors.initials: N
authors.lastname: Ben Baruch-Morgenstern
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, 69978, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Shik
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, 69978, Israel.
authors.forename: Itay
authors.initials: I
authors.lastname: Moshkovits
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, 69978, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Itan
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, 69978, Israel.
authors.forename: Danielle
authors.initials: D
authors.lastname: Karo-Atar
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229.
authors.forename: Carine
authors.initials: C
authors.lastname: Bouffi
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fulkerson
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Rashkovan
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, 69978, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay / Q000379:methods; D004804:Eosinophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D015848:Interleukin-5; D008565:Membrane Proteins; C105948:Pira1 protein, mouse; C105949:Pirb protein, mouse; D011518:Proto-Oncogene Proteins; D011971:Receptors, Immunologic; D048049:Extracellular Signal-Regulated MAP Kinases