{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T15:07:53Z","timestamp":1747148873990,"version":"3.40.5"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,11,16]],"date-time":"2018-11-16T00:00:00Z","timestamp":1542326400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000261","name":"Multiple Sclerosis Society of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000261","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>During inflammatory processes of the central nervous system, helper T cells have the capacity to cross the blood\u2013brain barrier and injure or kill neural cells through cytotoxic mechanisms. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is part of the astrocyte cytoskeleton that can become fragmented in neuroinflammatory conditions. The mechanism of action by which helper T cells with cytotoxic properties injure astrocytes is not completely understood. Primary human astrocytes were obtained from fetal brain tissue. Human helper (CD4<jats:sup>+<\/jats:sup>) T cells were isolated from peripheral blood mononuclear cells and activated with the superantigen staphylococcal enterotoxin E (SEE). Granzyme B was detected by enzyme linked immunosorbent assay and intracellular flow cytometry. GFAP fragmentation was monitored by western blotting. Cell death was monitored by lactic acid dehydrogenase release and terminal biotin\u2010dUTP nick labeling (TUNEL). Astrocyte migration was monitored by scratch assay. Adult human oligodendrocytes were cultured with sublethally injured astrocytes to determine support function. Helper T cells activated with SEE expressed granzyme B but not perforin. Helper T cells released granzyme B upon contact with astrocytes and caused GFAP fragmentation in a caspase\u2010dependent, MHCII\u2010independent manner. Sublethally injured astrocytes were not apoptotic; however, their processes were thin and elongated, their migration was attenuated, and their ability to support oligodendrocytes was reduced in vitro. Helper T cells can release granzyme B causing sublethal injury to astrocytes, which compromises the supportive functions of astrocytes. Blocking these pathways may lead to improved resolution of neuroinflammatory lesions.<\/jats:p>","DOI":"10.1002\/glia.23503","type":"journal-article","created":{"date-parts":[[2018,11,16]],"date-time":"2018-11-16T10:26:12Z","timestamp":1542363972000},"page":"582-593","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Helper CD4 T cells expressing granzyme B cause glial fibrillary acidic protein fragmentation in astrocytes in an MHCII\u2010independent manner"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4713-683X","authenticated-orcid":false,"given":"Brandon","family":"Stopnicki","sequence":"first","affiliation":[{"name":"Department of Exercise Science, Department of Biology PERFORM Centre, Concordia University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manon","family":"Blain","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute, and McGill University  Montreal Quebec Canada"},{"name":"Neuroimmunology Unit McGill University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiao\u2010Ling","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute, and McGill University  Montreal Quebec Canada"},{"name":"Neuroimmunology Unit McGill University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy E.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute, and McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack P.","family":"Antel","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute, and McGill University  Montreal Quebec Canada"},{"name":"Neuroimmunology Unit McGill University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke M.","family":"Healy","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute, and McGill University  Montreal Quebec Canada"},{"name":"Neuroimmunology Unit McGill University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Darlington","sequence":"additional","affiliation":[{"name":"Department of Exercise Science, Department of Biology PERFORM Centre, Concordia University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,11,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20518"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.1992.tb00812.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03239"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22443"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2011.11.006"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.04.012"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.14166"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181ef3be4"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181772cf6"},{"issue":"1","key":"e_1_2_7_11_1","first-page":"22","article-title":"Granzyme B contributes to the optimal graft\u2010versus\u2010tumor effect mediated by conventional CD4 T cells","volume":"1","author":"Du W.","year":"2016","journal-title":"Journal of Immunology Research and Therapy"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00612-4"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.1.368"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20938"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0340051"},{"issue":"157","key":"e_1_2_7_16_1","first-page":"1","article-title":"Granzyme B\u2010inhibitor serpina3n induces neuroprotection in vitro and in vivo","volume":"12","author":"Haile Y.","year":"2015","journal-title":"Journal of Neuroinflammation"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-8411(92)90002-8"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-8411(92)90003-9"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.02.006"},{"issue":"10","key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.4049\/jimmunol.156.10.3678","article-title":"Concanamycin a, a powerful tool for characterization and estimation of contribution of perforin\u2010 and fas\u2010based lytic pathways in cell\u2010mediated cytotoxicity","volume":"156","author":"Kataoka T.","year":"1996","journal-title":"Journal of Immunology"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1651"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90421-9"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164164"},{"issue":"131","key":"e_1_2_7_24_1","first-page":"1","article-title":"Protease\u2010activated receptor\u20101 activation by granzyme B causes neurotoxicity that is augmented by interleukin\u20101\u03b2","volume":"14","author":"Lee P. R.","year":"2017","journal-title":"Journal of Neuroinflammation"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2017.05.012"},{"issue":"1","key":"e_1_2_7_26_1","first-page":"251","article-title":"Experimental autoimmune encephalomyelitis in mice lacking glial fibrillary acidic protein is characterized by a more severe clinical course and an infiltrative central nervous system lesion","volume":"152","author":"Liedtke W.","year":"1998","journal-title":"The American Journal of Pathology"},{"issue":"36","key":"e_1_2_7_27_1","first-page":"1","article-title":"Granzyme B secretion by human memory CD4 T cells is less strictly regulated compared to memory CD8 T cells","volume":"15","author":"Lin L.","year":"2014","journal-title":"BMC Immunology"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.10.094"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2008.03.001"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-014-0094-5"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1592-15.2015"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050798"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1986.tb13079.x"},{"issue":"11","key":"e_1_2_7_34_1","doi-asserted-by":"crossref","first-page":"6543","DOI":"10.4049\/jimmunol.162.11.6543","article-title":"Potential role of CD4+ T cell\u2010mediated apoptosis of activated astrocytes in theiler's virus\u2010induced demyelination","volume":"162","author":"Palma J. P.","year":"1999","journal-title":"Journal of Immunology"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2009.02.004"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22948"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.5.855"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02059-X"},{"issue":"52199","key":"e_1_2_7_39_1","first-page":"1","article-title":"Detecting glycogen in peripheral blood mononuclear cells with periodic acid schiff staining","volume":"94","author":"Tabatabaei Shafiei M.","year":"2014","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20486"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-5022fje"}],"container-title":["Glia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fglia.23503","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23503","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T02:31:21Z","timestamp":1694658681000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/glia.23503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,16]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1002\/glia.23503"],"URL":"https:\/\/doi.org\/10.1002\/glia.23503","archive":["Portico"],"relation":{},"ISSN":["0894-1491","1098-1136"],"issn-type":[{"type":"print","value":"0894-1491"},{"type":"electronic","value":"1098-1136"}],"subject":[],"published":{"date-parts":[[2018,11,16]]},"assertion":[{"value":"2017-10-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}