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In this function they strictly control T-cell entry into the CNS. T cells can reach the CNS by either crossing the endothelial blood\u2013brain barrier (BBB) or the epithelial blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4\n                      <jats:sup>+<\/jats:sup>\n                      T-cell subsets across the BBB versus the BCSFB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human in vitro models of the BBB and BCSFB were employed to study the migration of circulating and CNS-entry experienced CD4\n                      <jats:sup>+<\/jats:sup>\n                      T helper cell subsets (Th1, Th1*, Th2, Th17) across the BBB and BCSFB under inflammatory and non-inflammatory conditions in vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>While under non-inflammatory conditions Th1* and Th1 cells preferentially crossed the BBB, under inflammatory conditions the migration rate of all Th subsets across the BBB was comparable. The migration of all Th subsets across the BCSFB from the same donor was 10- to 20-fold lower when compared to their migration across the BBB. Interestingly, Th17 cells preferentially crossed the BCSFB under both, non-inflamed and inflamed conditions. Barrier-crossing experienced Th cells sorted from CSF of MS patients showed migratory characteristics indistinguishable from those of circulating Th cells of healthy donors. All Th cell subsets could additionally cross the BCSFB from the CSF to ChP stroma side. T-cell migration across the BCSFB involved epithelial ICAM-1 irrespective of the direction of migration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our observations underscore that different Th subsets may use different anatomical routes to enter the CNS during immune surveillance versus neuroinflammation with the BCSFB establishing a tighter barrier for T-cell entry into the CNS compared to the BBB. In addition, CNS-entry experienced Th cell subsets isolated from the CSF of MS patients do not show an increased ability to cross the brain barriers when compared to circulating Th cell subsets from healthy donors underscoring the active role of the brain barriers in controlling T-cell entry into the CNS. Also we identify ICAM-1 to mediate T cell migration across the BCSFB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12987-019-0165-2","type":"journal-article","created":{"date-parts":[[2020,2,2]],"date-time":"2020-02-02T19:02:15Z","timestamp":1580670135000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro"],"prefix":"10.1186","volume":"17","author":[{"given":"Hideaki","family":"Nishihara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasha","family":"Soldati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Mossu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rosito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henriette","family":"Rudolph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Muller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Latorre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Sallusto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Sospedra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Tenenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Schroten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Gosselet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3059-9846","authenticated-orcid":false,"given":"Britta","family":"Engelhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,3]]},"reference":[{"issue":"2","key":"165_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/ni.3666","volume":"18","author":"B Engelhardt","year":"2017","unstructured":"Engelhardt B, Vajkoczy P, Weller RO. 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All patients gave their consents. For the usage of HIBCPP model, Approval was obtained by the local ethics committee of the Medical Faculty of Mannheim, Heidelberg University (2009-327N-MA). Human primary cell protocols were approved by the Swiss Federal Office of Public Health (authorisation N. A000197\/2 to F. Sallusto). Informed consent from blood donors was approved by the local ethical committee (Comitato Etico Cantonale,\n                      \n                      , authorization n. CE3428).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"RM received unrestricted Grants from Biogen and Novartis, personal compensation for lecture or advisory board functions from Biogen, Merck, Novartis, Roche, Sanofi Aventis, Teva, Cell-Protect and Neuway. He is a co-founder and co-owner of Cellerys, a startup company of the University of Zurich. RM is co-inventor and patent holder on patents related to antigen-specific tolerization, treatment\/vaccination of PML and the use of daclizumab as a treatment of multiple sclerosis. BE received a Grant from Biogen to study extended natalizumab dosing on T-cell migration into the CNS.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}