{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:20:37Z","timestamp":1791300037256,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2017,10,1]],"date-time":"2017-10-01T00:00:00Z","timestamp":1506816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The proper regulation of ICOS and ICOS ligand (ICOSL) has been shown to be essential for maintaining proper immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant Ab production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that a disintegrin and metalloproteinase (ADAM)10 is the primary physiological sheddase of ICOSL in mice and humans. Using an in vivo system in which ADAM10 is deleted only on B cells, elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wild-type mice, interaction of ICOS\/ICOSL results in ADAM10-induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper development and TH2 polarization, as seen in a house dust mite exposure model. In addition, enhanced TH1 and TH17 immune responses are seen in experimental autoimmune encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and rescues, at least in part, T follicular helper numbers and the abnormal Ab production previously reported in these mice. Overall, we propose a novel regulation of the ICOS\/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL, as well as indirectly regulating ICOS, thus controlling ICOS\/ICOSL-dependent responses.<\/jats:p>","DOI":"10.4049\/jimmunol.1700833","type":"journal-article","created":{"date-parts":[[2017,8,17]],"date-time":"2017-08-17T00:40:22Z","timestamp":1502930422000},"page":"2305-2315","source":"Crossref","is-referenced-by-count":39,"title":["ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses"],"prefix":"10.1093","volume":"199","author":[{"given":"Joseph C","family":"Lownik","sequence":"first","affiliation":[{"name":"Center for Clinical and Translational Research, School of Medicine, Virginia Commonwealth University , Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea J","family":"Luker","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University , Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-0950","authenticated-orcid":false,"given":"Sheela R","family":"Damle","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University , Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren Folgosa","family":"Cooley","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, School of Medicine, Virginia Commonwealth University , Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-5872","authenticated-orcid":false,"given":"Riham","family":"El Sayed","sequence":"additional","affiliation":[{"name":"Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London , London EC1M 6BQ,","place":["United Kingdom"]},{"name":"Department of Clinical and Chemical Pathology, Kasr Al-Ainy Faculty of Medicine, Cairo University , Cairo 11562,","place":["Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0572-8151","authenticated-orcid":false,"given":"Andreas","family":"Hutloff","sequence":"additional","affiliation":[{"name":"German Rheumatism Research Centre Berlin , 10117 Berlin,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1326-5051","authenticated-orcid":false,"given":"Costantino","family":"Pitzalis","sequence":"additional","affiliation":[{"name":"Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London , London EC1M 6BQ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca K","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University , Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohey Eldin M","family":"El Shikh","sequence":"additional","affiliation":[{"name":"Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London , London EC1M 6BQ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4791-2694","authenticated-orcid":false,"given":"Daniel H","family":"Conrad","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University , Richmond, VA 23298"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,10,1]]},"reference":[{"key":"2025030614473729100_r1","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1091\/mbc.e08-11-1135","article-title":"ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha","volume":"20","author":"Le Gall","year":"2009","journal-title":"Mol. 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