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The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2013
Author Marczynska Joanna, Ozga Aleksandra, Wlodarczyk Agnieszka, Majchrzak-Gorecka Monika, Kulig Paulina, Banas Magdalena, Michalczyk-Wetula Dominika, Majewski Pawel, Hutloff Andreas, Hutloff Andreas, Schwarz Jeanette, Chalaris Athena, Scheller Jürgen, Scheller Jürgen, Rose-John Stefan, Cichy Joanna,
Project Cell Migration
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Original article (peer-reviewed)

Journal Journal of Immunology
Volume (Issue) 193(6)
Page(s) 2753 - 2763
Title of proceedings Journal of Immunology
DOI 10.4049/jimmunol.1302893

Abstract

© 2014 by The American Association of Immunologists, Inc. 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 (ADAM17ex/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 classswitched 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 ADAM17ex/exmice 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.
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