title: The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses.
abstract: Immune cells regulate cell surface receptor expression during their maturation, activation, and motility. Although many of these receptors are regulated largely at the level of expression, protease-mediated ectodomain shedding represents an alternative means of refashioning the surface of immune cells. Shedding is largely attributed to a family of a disintegrin and metalloprotease domain (ADAM) metalloproteases, including ADAM17. Although ADAM17 is well known to contribute to the innate immune response, mainly by releasing TNF-α, much less is known about whether/how this metalloprotease regulates adaptive immunity. To determine whether ADAM17 contributes to regulating adaptive immune responses, we took advantage of ADAM17 hypomorphic (ADAM17(ex/ex)) mice, in which ADAM17 expression is reduced by 90-95% compared with wild-type littermates. In this study, we show that that ADAM17 deficiency results in spleen and lymph node enlargement, as well as increased levels of Ag-specific class-switched Ig production following immunization with OVA together with anti-CD40 mAbs and polyinosinic-polycytidylic acid. Moreover, we demonstrate that the costimulatory ligand ICOS ligand (ICOSL) is selectively downregulated on the surface of B cells in an ADAM17-specific manner, although it is not proteolitically processed by recombinant ADAM17 in vitro. Finally, we show that higher cell surface levels of ICOSL in ADAM17(ex/ex) mice may contribute to the development of excessive Ab responses. Therefore, our data suggest a functional link between ADAM17 and ICOSL in controlling adaptive immune responses.
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Joanna
authors.initials: J
authors.lastname: Marczynska
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ozga
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wlodarczyk
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Monika
authors.initials: M
authors.lastname: Majchrzak-Gorecka
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Paulina
authors.initials: P
authors.lastname: Kulig
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Banas
authors.affiliation: Department of Biophysics, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Michalczyk-Wetula
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
authors.forename: Pawel
authors.initials: P
authors.lastname: Majewski
authors.affiliation: Robert Koch Institute, 13353 Berlin, Germany; German Rheumatism Research Center, 10117 Berlin, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Hutloff
authors.affiliation: Department of Biochemistry, Medical Faculty, Christian Albrechts University, 24118 Kiel, Germany; and.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Schwarz
authors.affiliation: Department of Biochemistry, Medical Faculty, Christian Albrechts University, 24118 Kiel, Germany; and.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: Department of Biochemistry, Medical Faculty, Christian Albrechts University, 24118 Kiel, Germany; and Institute of Biochemistry and Molecular Biology, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Department of Biochemistry, Medical Faculty, Christian Albrechts University, 24118 Kiel, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; Joanna.Cichy@uj.edu.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cichy
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology*; D000072198:ADAM17 Protein; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019013:CD40 Antigens / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D056724:Immunity, Humoral; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000096:biosynthesis / Q000276:immunology*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011070:Poly I-C / Q000276:immunology; D013154:Spleen / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C400230:Icosl protein, mouse; D007132:Immunoglobulin Isotypes; D060945:Inducible T-Cell Co-Stimulator Ligand; D010047:Ovalbumin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D011070:Poly I-C