{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T18:20:46Z","timestamp":1790965246965,"version":"4.1.0"},"reference-count":130,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T00:00:00Z","timestamp":1517875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP16252"],"award-info":[{"award-number":["GGP16252"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009885","name":"Regione Piemonte","doi-asserted-by":"publisher","award":["TIPSO"],"award-info":[{"award-number":["TIPSO"]}],"id":[{"id":"10.13039\/501100009885","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universit\u00e0 Piemonte Orientale","award":["Ricerca locale 2016"],"award-info":[{"award-number":["Ricerca locale 2016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (\u03b1L\u03b22 integrin) and VLA-4 (\u03b14\u03b21 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of \u03b14\u03b27 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research.<\/jats:p>","DOI":"10.3390\/ijms19020485","type":"journal-article","created":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T14:31:17Z","timestamp":1517927477000},"page":"485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Integrins in T Cell Physiology"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3981-7099","authenticated-orcid":false,"given":"Alessandra","family":"Bertoni","sequence":"first","affiliation":[{"name":"Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Alabiso","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Eastern Piedmont, Novara\u2014Italy and Oncology Division, University Hospital \u201cMaggiore della Carit\u00e0\u201d, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Galetto","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Eastern Piedmont, Novara 28100\u2014Italy and Palliative Care Division, A.S.L., 13100 Vercelli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Baldanzi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,6]]},"reference":[{"key":"ref_1","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":"ref_2","doi-asserted-by":"crossref","first-page":"8235","DOI":"10.1021\/bi300925r","article-title":"Distinct sites within the vascular cell adhesion molecule-1 (VCAM-1) cytoplasmic domain regulate VCAM-1 activation of calcium fluxes versus Rac1 during leukocyte transendothelial migration","volume":"51","author":"Marchese","year":"2012","journal-title":"Biochemistry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.4049\/jimmunol.171.4.2099","article-title":"Intracellular domain of brain endothelial intercellular adhesion molecule-1 is essential for T lymphocyte-mediated signaling and migration","volume":"171","author":"Greenwood","year":"2003","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1242\/jcs.03098","article-title":"Integrin ligands at a glance","volume":"119","author":"Humphries","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.it.2013.03.004","article-title":"Immunological Genome Project and systems immunology","volume":"34","author":"Shay","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"30","DOI":"10.7150\/thno\/v01p0030","article-title":"Why integrin as a primary target for imaging and therapy","volume":"1","author":"Niu","year":"2011","journal-title":"Theranostics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5983","DOI":"10.4049\/jimmunol.1400889","article-title":"A signal integration model of thymic selection and natural regulatory T cell commitment","volume":"193","author":"Khailaie","year":"2014","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1189\/jlb.1003455","article-title":"Molecular mechanisms governing thymocyte migration: Combined role of chemokines and extracellular matrix","volume":"75","author":"Savino","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1073\/pnas.1314209111","article-title":"Dynamic control of \u03b21 integrin adhesion by the plexinD1-sema3E axis","volume":"111","author":"Choi","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3517","DOI":"10.4049\/jimmunol.149.11.3517","article-title":"Expression of VLA-4 on thymocytes. Maturation stage-associated transition and its correlation with their capacity to adhere to thymic stromal cells","volume":"149","author":"Sawada","year":"1992","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.4049\/jimmunol.1301820","article-title":"CD11a is essential for normal development of hematopoietic intermediates","volume":"193","author":"Bose","year":"2014","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5685","DOI":"10.1073\/pnas.88.13.5685","article-title":"Adhesion of immature thymocytes to thymic stromal cells through fibronectin molecules and its significance for the induction of thymocyte differentiation","volume":"88","author":"Utsumi","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1182\/blood.V89.7.2461","article-title":"Vascular cell adhesion molecule-1 is expressed by cortical thymic epithelial cells and mediates thymocyte adhesion. Implications for the function of alpha4beta1 (VLA4) integrin in T-cell development","volume":"89","author":"Salomon","year":"1997","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1471-2164-11-S5-S2","article-title":"RNA interference-mediated knockdown of CD49e (\u03b15 integrin chain) in human thymic epithelial cells modulates the expression of multiple genes and decreases thymocyte adhesion","volume":"11","author":"Nogueira","year":"2010","journal-title":"BMC Genom."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1111\/imm.12533","article-title":"Regulatory T-cell development and function are impaired in mice lacking membrane expression of full length intercellular adhesion molecule-1","volume":"146","author":"Gottrand","year":"2015","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.molimm.2007.05.016","article-title":"Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) provide co-stimulation in positive selection along with survival of selected thymocytes","volume":"45","author":"Paessens","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1046\/j.1365-2567.1998.00636.x","article-title":"Enhancement of activation-induced cell death by fibronectin in murine CD4+ CD8+ thymocytes","volume":"95","author":"Takayama","year":"1998","journal-title":"Immunology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1083\/jcb.144.3.563","article-title":"Laminin 5 in the human thymus: Control of T cell proliferation via alpha6beta4 integrins","volume":"144","author":"Ticchioni","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"192","DOI":"10.4049\/jimmunol.165.1.192","article-title":"Epithelial cell-specific laminin 5 is required for survival of early thymocytes","volume":"165","author":"Kim","year":"2000","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4354","DOI":"10.4049\/jimmunol.169.8.4354","article-title":"Stromal cells provide the matrix for migration of early lymphoid progenitors through the thymic cortex","volume":"169","author":"Prockop","year":"2002","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1038\/ncomms2105","article-title":"Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus","volume":"3","author":"Ueda","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1083\/jcb.131.2.495","article-title":"Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway","volume":"131","author":"Nieto","year":"1995","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.137.2.493","article-title":"ICAMs redistributed by chemokines to cellular uropods as a mechanism for recruitment of T lymphocytes","volume":"137","author":"Montoya","year":"1997","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1128\/MCB.01177-13","article-title":"Miro-1 links mitochondria and microtubule Dynein motors to control lymphocyte migration and polarity","volume":"34","author":"Morlino","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.immuni.2008.12.020","article-title":"Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin","volume":"30","author":"Shulman","year":"2009","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13119","DOI":"10.1038\/ncomms13119","article-title":"Coordinated integrin activation by actin-dependent force during T-cell migration","volume":"7","author":"Nordenfelt","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.4049\/jimmunol.160.6.2967","article-title":"Bi-directional induction of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 during T lymphoma\/endothelial cell contact: Implication of ICAM-1","volume":"160","author":"Aoudjit","year":"1998","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1182\/blood-2009-08-237917","article-title":"Distinct roles for LFA-1 affinity regulation during T-cell adhesion, diapedesis, and interstitial migration in lymph nodes","volume":"115","author":"Park","year":"2010","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/sj.emboj.7601959","article-title":"Intermediate-affinity LFA-1 binds alpha-actinin-1 to control migration at the leading edge of the T cell","volume":"27","author":"Stanley","year":"2008","journal-title":"EMBO J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1083\/jcb.200412032","article-title":"A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes","volume":"170","author":"Smith","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Svensson, L., Stanley, P., Willenbrock, F., and Hogg, N. (2012). The G\u03b1q\/11 proteins contribute to T lymphocyte migration by promoting turnover of integrin LFA-1 through recycling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038517"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1242\/bio.20122824","article-title":"A role for Rap2 in recycling the extended conformation of LFA-1 during T cell migration","volume":"1","author":"Stanley","year":"2012","journal-title":"Biol. Open"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1002\/eji.1830231111","article-title":"Characterization of two new CD18 alleles causing severe leukocyte adhesion deficiency","volume":"23","author":"Nueda","year":"1993","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1084\/jem.160.6.1901","article-title":"Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis","volume":"160","author":"Springer","year":"1984","journal-title":"J. Exp. Med."},{"key":"ref_35","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":"ref_36","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1084\/jem.177.1.185","article-title":"Lymphocyte function-associated antigen 1 dominates very late antigen 4 in binding of activated T cells to endothelium","volume":"177","author":"Weder","year":"1993","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.4049\/jimmunol.168.4.1934","article-title":"The role of E-selectin, P-selectin, and very late activation antigen-4 in T lymphocyte migration to dermal inflammation","volume":"168","author":"Issekutz","year":"2002","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21053","DOI":"10.1074\/jbc.M116.733709","article-title":"Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated \u03b14\u03b21 Integrins on T Cells","volume":"291","author":"Borgman","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"359","DOI":"10.4049\/jimmunol.0803388","article-title":"Activated integrin VLA-4 localizes to the lamellipodia and mediates T cell migration on VCAM-1","volume":"183","author":"Hyun","year":"2009","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1006\/excr.2000.5002","article-title":"Differential induction of gelatinase B (MMP-9) and gelatinase A (MMP-2) in T lymphocytes upon alpha(4)beta(1)-mediated adhesion to VCAM-1 and the CS-1 peptide of fibronectin","volume":"260","author":"Yakubenko","year":"2000","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1096\/fj.04-3574fje","article-title":"Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells","volume":"19","author":"Segarra","year":"2005","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1084\/jem.20011502","article-title":"Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues","volume":"195","author":"Campbell","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.4049\/jimmunol.0901903","article-title":"CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors","volume":"184","author":"Ferguson","year":"2010","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/eji.200636575","article-title":"Induction of organ-selective CD4+ regulatory T cell homing","volume":"37","author":"Siewert","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4307","DOI":"10.4049\/jimmunol.169.8.4307","article-title":"P-, E-, and L-selectin mediate migration of activated CD8+ T lymphocytes into inflamed skin","volume":"169","author":"Hirata","year":"2002","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"963","DOI":"10.4049\/jimmunol.161.2.963","article-title":"CD4+ T cells migrate into inflamed skin only if they express ligands for E- and P-selectin","volume":"161","author":"Tietz","year":"1998","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/eji.201646722","article-title":"\u03b14 \u03b21 integrin promotes accumulation of tissue-resident memory CD8(+) T cells in salivary glands","volume":"47","author":"Woyciechowski","year":"2017","journal-title":"Eur. J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1084\/jem.193.6.741","article-title":"Conditional vascular cell adhesion molecule 1 deletion in mice: Impaired lymphocyte migration to bone marrow","volume":"193","author":"Koni","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_49","first-page":"97","article-title":"Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue","volume":"151","author":"Briskin","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3302","DOI":"10.1002\/eji.201545632","article-title":"Migration of encephalitogenic CD8 T cells into the central nervous system is dependent on the \u03b14\u03b21-integrin","volume":"45","author":"Pignolet","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4396","DOI":"10.4049\/jimmunol.161.8.4396","article-title":"Endothelial selectins and alpha4 integrins regulate independent pathways of T lymphocyte recruitment in the pulmonary immune response","volume":"161","author":"Wolber","year":"1998","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1073\/pnas.0808909106","article-title":"Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity","volume":"106","author":"Bauer","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature01726","article-title":"Selective imprinting of gut-homing T cells by Peyer\u2019s patch dendritic cells","volume":"424","author":"Mora","year":"2003","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"G1257","DOI":"10.1152\/ajpgi.00266.2007","article-title":"CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow","volume":"294","author":"Miles","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/372190a0","article-title":"Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin","volume":"372","author":"Cepek","year":"1994","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.immuni.2013.08.019","article-title":"Transforming growth factor-\u03b2 signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention","volume":"39","author":"Zhang","year":"2013","journal-title":"Immunity"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.sder.2010.01.001","article-title":"Assessing long-term drug safety: Lessons (re) learned from raptiva","volume":"29","author":"Seminara","year":"2010","journal-title":"Semin. Cutan. Med. Surg."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3727\/096368912X657350","article-title":"Inhibition of recall responses through complementary therapies targeting CD8+ T-cell- and alloantibody-dependent allocytotoxicity in sensitized transplant recipients","volume":"22","author":"Zimmerer","year":"2013","journal-title":"Cell Transplant."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"599","DOI":"10.3727\/096368908786092757","article-title":"Monotherapy with anti-LFA-1 monoclonal antibody promotes long-term survival of rat islet xenografts","volume":"17","author":"Tredget","year":"2008","journal-title":"Cell Transplant."},{"key":"ref_60","first-page":"442","article-title":"Rovelizumab (ICOS Corp)","volume":"3","author":"Jones","year":"2000","journal-title":"IDrugs"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/nm0810-863","article-title":"A double agent in cancer: Stopping macrophages wounds tumors","volume":"16","author":"Qualls","year":"2010","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1084\/jem.20031579","article-title":"Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis","volume":"199","author":"Viglietta","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/0092-8674(90)90661-W","article-title":"VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4\/fibronectin binding site","volume":"60","author":"Elices","year":"1990","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1517\/14712598.2016.1158807","article-title":"Etrolizumab for ulcerative colitis: The new kid on the block?","volume":"16","author":"Makker","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3233\/HAB-1997-8102","article-title":"Humanization of a mouse antibody against human alpha-4 integrin: A potential therapeutic for the treatment of multiple sclerosis","volume":"8","author":"Yednock","year":"1997","journal-title":"Hum. Antib."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0165-5728(94)00165-K","article-title":"A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis","volume":"58","author":"Kent","year":"1995","journal-title":"J. Neuroimmunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1056\/NEJMoa020696","article-title":"A controlled trial of natalizumab for relapsing multiple sclerosis","volume":"348","author":"Miller","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1056\/NEJMoa044397","article-title":"A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis","volume":"354","author":"Polman","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1056\/NEJMoa051847","article-title":"Progressive multifocal leukoencephalopathy in a patient treated with natalizumab","volume":"353","author":"Atlas","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/25764","article-title":"Three-dimensional segregation of supramolecular activation clusters in T cells","volume":"395","author":"Monks","year":"1998","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"a002311","DOI":"10.1101\/cshperspect.a002311","article-title":"Understanding the structure and function of the immunological synapse","volume":"2","author":"Dustin","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11058","DOI":"10.1073\/pnas.0307927101","article-title":"VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses","volume":"101","author":"Mittelbrunn","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1158\/2326-6066.CIR-14-0161","article-title":"The immunological synapse","volume":"2","author":"Dustin","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1091\/mbc.e11-08-0731","article-title":"Actin retrograde flow and actomyosin II arc contraction drive receptor cluster dynamics at the immunological synapse in Jurkat T cells","volume":"23","author":"Yi","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20296","DOI":"10.1073\/pnas.0710258105","article-title":"Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells","volume":"104","author":"Kaizuka","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1083\/jcb.201603080","article-title":"Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse","volume":"215","author":"Murugesan","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1083\/jcb.201406121","article-title":"F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse","volume":"208","author":"Comrie","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1083\/jcb.201406120","article-title":"The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility","volume":"208","author":"Comrie","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1084\/jem.20151088","article-title":"Micro-adhesion rings surrounding TCR microclusters are essential for T cell activation","volume":"213","author":"Sakuma","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.4049\/jimmunol.179.3.1616","article-title":"LFA-1-mediated T cell costimulation through increased localization of TCR\/class II complexes to the central supramolecular activation cluster and exclusion of CD45 from the immunological synapse","volume":"179","author":"Graf","year":"2007","journal-title":"J. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1039\/C5IB00032G","article-title":"Micropatterning of TCR and LFA-1 ligands reveals complementary effects on cytoskeleton mechanics in T cells","volume":"7","author":"Tabdanov","year":"2015","journal-title":"Integr. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e23190","DOI":"10.7554\/eLife.23190","article-title":"Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity","volume":"6","author":"Saitakis","year":"2017","journal-title":"eLife"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Husson, J., Chemin, K., Bohineust, A., Hivroz, C., and Henry, N. (2011). Force generation upon T cell receptor engagement. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019680"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.immuni.2007.12.016","article-title":"Intercellular adhesion molecule-1-dependent stable interactions between T cells and dendritic cells determine CD8+ T cell memory","volume":"28","author":"Scholer","year":"2008","journal-title":"Immunity"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1074-7613(00)80376-3","article-title":"Distinct roles for LFA-1 and CD28 during activation of naive T cells: Adhesion versus costimulation","volume":"7","author":"Bachmann","year":"1997","journal-title":"Immunity"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"665","DOI":"10.4049\/jimmunol.148.3.665","article-title":"Intercellular adhesion molecule-2, a second counter-receptor for CD11a\/CD18 (leukocyte function-associated antigen-1), provides a costimulatory signal for T-cell receptor-initiated activation of human T cells","volume":"148","author":"Damle","year":"1992","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/ni.2364","article-title":"Integration of the movement of signaling microclusters with cellular motility in immunological synapses","volume":"13","author":"Beemiller","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.cell.2007.03.037","article-title":"Opposing effects of PKCtheta and WASp on symmetry breaking and relocation of the immunological synapse","volume":"129","author":"Sims","year":"2007","journal-title":"Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3817","DOI":"10.1083\/jcb.201609072","article-title":"A novel intracellular pool of LFA-1 is critical for asymmetric CD8(+) T cell activation and differentiation","volume":"216","author":"Capece","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/341619a0","article-title":"T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1","volume":"341","author":"Dustin","year":"1989","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.1128\/MCB.00136-07","article-title":"WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse","volume":"27","author":"Nolz","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/345250a0","article-title":"Regulated expression and binding of three VLA (beta 1) integrin receptors on T cells","volume":"345","author":"Shimizu","year":"1990","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/eji.1830210719","article-title":"Remote T cell co-stimulation via LFA-1\/ICAM-1 and CD2\/LFA-3: Demonstration with immobilized ligand\/mAb and implication in monocyte-mediated co-stimulation","volume":"21","author":"Shimizu","year":"1991","journal-title":"Eur. J. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.4049\/jimmunol.162.3.1367","article-title":"TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization","volume":"162","author":"Sedwick","year":"1999","journal-title":"J. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.4049\/jimmunol.1600832","article-title":"CD8+ Effector T Cell Migration to Pancreatic Islet Grafts Is Dependent on Cognate Antigen Presentation by Donor Graft Cells","volume":"197","author":"Zhang","year":"2016","journal-title":"J. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"14809","DOI":"10.1038\/ncomms14809","article-title":"Cognate antigen engagement on parenchymal cells stimulates CD8(+) T cell proliferation in situ","volume":"8","author":"Sutherland","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5183","DOI":"10.4049\/jimmunol.162.9.5183","article-title":"Signaling pathways activated by leukocyte function-associated Ag-1-dependent costimulation","volume":"162","author":"Ni","year":"1999","journal-title":"J. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1073\/pnas.90.15.7099","article-title":"Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation","volume":"90","author":"Kanner","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.4049\/jimmunol.149.12.3872","article-title":"Costimulation of T cell receptor\/CD3-mediated activation of resting human CD4+ T cells by leukocyte function-associated antigen-1 ligand intercellular cell adhesion molecule-1 involves prolonged inositol phospholipid hydrolysis and sustained increase of intracellular Ca2+ levels","volume":"149","author":"Bonvini","year":"1992","journal-title":"J. Immunol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.4049\/jimmunol.166.11.6523","article-title":"LFA-1-mediated costimulation of CD8+ T cell proliferation requires phosphatidylinositol 3-kinase activity","volume":"166","author":"Ni","year":"2001","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.4049\/jimmunol.175.4.2201","article-title":"Lack of ICAM-1 on APCs during T cell priming leads to poor generation of central memory cells","volume":"175","author":"Parameswaran","year":"2005","journal-title":"J. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.4049\/jimmunol.151.5.2368","article-title":"Costimulation with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 augments activation-induced death of antigen-specific CD4+ T lymphocytes","volume":"151","author":"Damle","year":"1993","journal-title":"J. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4443","DOI":"10.4049\/jimmunol.173.7.4443","article-title":"LFA-1 on CD4+ T cells is required for optimal antigen-dependent activation in vivo","volume":"173","author":"Kandula","year":"2004","journal-title":"J. Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/(SICI)1521-4141(199901)29:01<45::AID-IMMU45>3.0.CO;2-I","article-title":"ICAM-1 and B7-1 provide similar but distinct costimulation for CD8+ T cells, while CD4+ T cells are poorly costimulated by ICAM-1","volume":"29","author":"Deeths","year":"1999","journal-title":"Eur. J. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/(SICI)1521-4141(199903)29:03<809::AID-IMMU809>3.0.CO;2-X","article-title":"ICAM-1 co-stimulation has differential effects on the activation of CD4+ and CD8+ T cells","volume":"29","author":"Chen","year":"1999","journal-title":"Eur. J. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"4826","DOI":"10.4049\/jimmunol.163.9.4826","article-title":"Defective CD8+ T cell activation and cytolytic function in the absence of LFA-1 cannot be restored by increased TCR signaling","volume":"163","author":"Shier","year":"1999","journal-title":"J. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/eji.1830180423","article-title":"Functional evidence that intercellular adhesion molecule-1 (ICAM-1) is a ligand for LFA-1-dependent adhesion in T cell-mediated cytotoxicity","volume":"18","author":"Makgoba","year":"1988","journal-title":"Eur. J. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"6403","DOI":"10.1073\/pnas.88.15.6403","article-title":"Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+ T lymphocytes","volume":"88","author":"Damle","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/j.1600-065X.2010.00917.x","article-title":"The power and the promise of restimulation-induced cell death in human immune diseases","volume":"236","author":"Snow","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/eji.1830230718","article-title":"Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a\/CD18-dependent mechanism","volume":"23","author":"Damle","year":"1993","journal-title":"Eur. J. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1165\/rcmb.2002-0105OC","article-title":"Integrin receptors are crucial for the restimulation of activated T lymphocytes","volume":"28","author":"Yarovinsky","year":"2003","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1182\/blood.V95.6.2044","article-title":"Engagement of the alpha2beta1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner","volume":"95","author":"Aoudjit","year":"2000","journal-title":"Blood"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1002\/1521-4141(200104)31:4<1228::AID-IMMU1228>3.0.CO;2-K","article-title":"Activation of beta(1) integrins mediates proliferation and inhibits apoptosis of intestinal CD4-positive lymphocytes","volume":"31","author":"Stallmach","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"9345495","DOI":"10.1155\/2016\/9345495","article-title":"Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo","volume":"2016","author":"Boggio","year":"2016","journal-title":"J. Immunol. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.4049\/jimmunol.165.9.4935","article-title":"Potent costimulation of effector T lymphocytes by human collagen type I","volume":"165","author":"Rao","year":"2000","journal-title":"J. Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1084\/jem.172.2.649","article-title":"Human CD4 helper T cell activation: Functional involvement of two distinct collagen receptors, 1F7 and VLA integrin family","volume":"172","author":"Dang","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1084\/jem.170.4.1133","article-title":"Activation of CD4 cells by fibronectin and anti-CD3 antibody. A synergistic effect mediated by the VLA-5 fibronectin receptor complex","volume":"170","author":"Matsuyama","year":"1989","journal-title":"J. Exp. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1084\/jem.172.4.1185","article-title":"VLA-4 mediates CD3-dependent CD4+ T cell activation via the CS1 alternatively spliced domain of fibronectin","volume":"172","author":"Nojima","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4049\/jimmunol.145.1.59","article-title":"Costimulation of proliferative responses of resting CD4+ T cells by the interaction of VLA-4 and VLA-5 with fibronectin or VLA-6 with laminin","volume":"145","author":"Shimizu","year":"1990","journal-title":"J. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1046\/j.1365-2567.1997.00237.x","article-title":"Cytotoxic T-lymphocyte interaction with fibronectin and vitronectin: Activated adhesion and cosignalling","volume":"91","author":"Ybarrondo","year":"1997","journal-title":"Immunology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1046\/j.1365-2567.2000.00995.x","article-title":"Fibronectin synthesis by activated T lymphocytes: Up-regulation of a surface-associated isoform with signalling function","volume":"99","author":"Wagner","year":"2000","journal-title":"Immunology"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1440-1711.2005.01318.x","article-title":"Fibronectin on activated T lymphocytes is bound to gangliosides and is present in detergent insoluble microdomains","volume":"83","author":"Blum","year":"2005","journal-title":"Immunol. Cell Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1006\/cimm.2001.1800","article-title":"Costimulation by extracellular matrix proteins determines the response to TCR ligation","volume":"210","author":"Adler","year":"2001","journal-title":"Cell. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1006\/bbrc.1998.9258","article-title":"Tenascin suppresses CD3-mediated T cell activation","volume":"250","author":"Hibino","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/imm.12424","article-title":"Antigen-induced regulation of T-cell motility, interaction with antigen-presenting cells and activation through endogenous thrombospondin-1 and its receptors","volume":"144","author":"Uzunel","year":"2015","journal-title":"Immunology"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.matbio.2013.02.009","article-title":"Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation","volume":"32","author":"Miller","year":"2013","journal-title":"Matrix Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1083\/jcb.200109098","article-title":"Interactions of thrombospondins with alpha4beta1 integrin and CD47 differentially modulate T cell behavior","volume":"157","author":"Li","year":"2002","journal-title":"J. Cell. Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1126\/science.287.5454.860","article-title":"Eta-1 (osteopontin): An early component of type-1 (cell-mediated) immunity","volume":"287","author":"Ashkar","year":"2000","journal-title":"Science"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/978-1-4939-6881-7_12","article-title":"Mathematical Modeling of Synaptic Patterns","volume":"1584","author":"Siokis","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Sun, M., and Zaman, M.H. (2017). Modeling, signaling and cytoskeleton dynamics: Integrated modeling-experimental frameworks in cell migration. Wiley Interdiscip. Rev. Syst. Biol. Med., 9.","DOI":"10.1002\/wsbm.1365"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:53:59Z","timestamp":1760194439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,6]]},"references-count":130,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["ijms19020485"],"URL":"https:\/\/doi.org\/10.3390\/ijms19020485","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,6]]}}}