{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T18:12:24Z","timestamp":1757700744153,"version":"3.37.3"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T00:00:00Z","timestamp":1563753600000},"content-version":"vor","delay-in-days":51,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leukocyte adhesion is important for the proper functioning of the immune system. While leukocyte homing is mediated by adhesion receptors, the activation of these receptors is modulated by intracellular signaling molecules. In Leukocyte Adhesion Deficiency Type 3, the loss of the kindlin-3 prevents the activation of Leukocyte Function-associated Antigen-1 (LFA-1), which leads to a defect in adhesion, causing recurrent infections and bleeding disorders. Here, we use Integrated Signaling Adhesive Dynamics, a computer model of leukocyte rolling and adhesion combined with a simulated intracellular signaling cascade, to predict the response of T cells to depletion of kindlin-3. Our model predicts that cell adhesion is hypersensitive to the amount of kindlin-3 in the cell, while the rolling velocity is independent of kindlin-3 concentration. In addition, our simulation predicted that the time to stop, an important metric of adhesion, would increase with decreasing kindlin-3 expression. These predictions were confirmed experimentally in experiments using Jurkat cells with reduced expression of kindlin-3. These results suggest that Adhesive Dynamics is a versatile tool for quantifying adhesion in the immune response and predicting the effects of engineering cellular components.<\/jats:p>","DOI":"10.1093\/intbio\/zyz024","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T11:42:46Z","timestamp":1563795766000},"page":"293-300","source":"Crossref","is-referenced-by-count":3,"title":["Adhesive dynamics simulations quantitatively predict effects of kindlin-3 deficiency on T-cell homing"],"prefix":"10.1093","volume":"11","author":[{"given":"Nicholas R","family":"Anderson","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dooyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3522-3154","authenticated-orcid":false,"given":"Daniel A","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,7,22]]},"reference":[{"key":"2019080810245954200_zyz024C1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nri2156","article-title":"Getting to the site of inflammation: the leukocyte adhesion cascade updated","volume":"7","author":"Ley","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"2019080810245954200_zyz024C2","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/nri2986","article-title":"The insider\u2019s guide to leukocyte integrin signalling and function","volume":"11","author":"Hogg","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"2019080810245954200_zyz024C3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/cvr\/cvv154","article-title":"Selectins: initiators of leucocyte adhesion and signalling at the vascular wall","volume":"107","author":"McEver","year":"2015","journal-title":"Cardiovasc Res"},{"key":"2019080810245954200_zyz024C4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2012.00127","article-title":"Chemokines and the signaling modules regulating integrin affinity","volume":"3","author":"Montresor","year":"2012","journal-title":"Front Immunol"},{"key":"2019080810245954200_zyz024C5","doi-asserted-by":"crossref","first-page":"4451","DOI":"10.4049\/jimmunol.1203179","article-title":"Integrin regulation during leukocyte recruitment","volume":"190","author":"Herter","year":"2013","journal-title":"J Immunol"},{"key":"2019080810245954200_zyz024C6","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev.immunol.25.022106.141618","article-title":"Structural basis of integrin regulation and signaling","volume":"25","author":"Luo","year":"2007","journal-title":"Annu Rev Immunol"},{"key":"2019080810245954200_zyz024C7","doi-asserted-by":"crossref","first-page":"18640","DOI":"10.1074\/jbc.M109.085746","article-title":"The integrin co-activator kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell","volume":"285","author":"Bialkowska","year":"2010","journal-title":"J Biol Chem"},{"key":"2019080810245954200_zyz024C8","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nm1722","article-title":"Kindlin-3 is essential for integrin activation and platelet aggregation","volume":"14","author":"Moser","year":"2008","journal-title":"Nat Med"},{"key":"2019080810245954200_zyz024C9","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nrm3624","article-title":"Talins and kindlins: partners in integrin-mediated adhesion","volume":"14","author":"Calderwood","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2019080810245954200_zyz024C10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11684-014-0317-3","article-title":"Talin and kindlin: the one-two punch in integrin activation","volume":"8","author":"Ye","year":"2014","journal-title":"Front Med China"},{"key":"2019080810245954200_zyz024C11","doi-asserted-by":"crossref","first-page":"4275","DOI":"10.1182\/blood-2011-08-373118","article-title":"Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation","volume":"119","author":"Lefort","year":"2012","journal-title":"Blood"},{"key":"2019080810245954200_zyz024C12","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nm.1921","article-title":"Kindlin-3 is required for \u03b22 integrin\u2013mediated leukocyte adhesion to endothelial cells","volume":"15","author":"Moser","year":"2009","journal-title":"Nat Med"},{"key":"2019080810245954200_zyz024C13","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1182\/blood-2009-04-218636","article-title":"Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions","volume":"114","author":"Manevich-Mendelson","year":"2009","journal-title":"Blood"},{"key":"2019080810245954200_zyz024C14","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nm.1931","article-title":"Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation","volume":"15","author":"Svensson","year":"2009","journal-title":"Nat Med"},{"key":"2019080810245954200_zyz024C15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1046\/j.1365-2249.2000.01277.x","article-title":"A novel point mutation in CD18 causing the expression of dysfunctional CD11\/CD18 leucocyte integrins in a patient with leucocyte adhesion deficiency (LAD","volume":"121","author":"Mathew","year":"2000","journal-title":"Clin Exp Immunol"},{"key":"2019080810245954200_zyz024C16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.molimm.2012.11.006","article-title":"The molecular basis of leukocyte recruitment and its deficiencies","volume":"55","author":"Schmidt","year":"2013","journal-title":"Mol Immunol"},{"key":"2019080810245954200_zyz024C17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2013.00108","article-title":"Biophysical description of multiple events contributing blood leukocyte arrest on endothelium","volume":"4","author":"Robert","year":"2013","journal-title":"Front Immunol"},{"key":"2019080810245954200_zyz024C18","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1182\/blood-2013-02-484998","article-title":"The 2 integrin-kindlin-3 interaction is essential for T-cell 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leukocyte adhesion deficiency type III","volume":"117","author":"Bergmeier","year":"2007","journal-title":"J Clin Invest"},{"key":"2019080810245954200_zyz024C40","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1016\/j.cub.2013.09.050","article-title":"The mechanism of kindlin-mediated activation of integrin \u03b1IIb\u03b23","volume":"23","author":"Ye","year":"2013","journal-title":"Current Biology"},{"key":"2019080810245954200_zyz024C41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.immuni.2007.01.002","article-title":"Force as a facilitator of integrin conformational changes during leukocyte arrest on blood vessels and antigen-presenting cells","volume":"26","author":"Alon","year":"2007","journal-title":"Immunity"},{"key":"2019080810245954200_zyz024C42","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1021\/bm060559c","article-title":"Force spectroscopy of LFA-1 and its ligands, ICAM-1 and 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