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Here, we characterize the functioning of brain-resident memory T cells (bTRM) in an animal model of viral infection. bTRM were subject to spontaneous homeostatic proliferation and were largely refractory to systemic immune cell depletion. After viral reinfection in mice, bTRM rapidly acquired cytotoxic effector function and prevented fatal brain infection, even in the absence of circulating CD8+ memory T cells. Presentation of cognate antigen on MHC-I was essential for bTRM-mediated protective immunity, which involved perforin- and IFN-\u03b3\u2013dependent effector mechanisms. These findings identify bTRM as an organ-autonomous defense system serving as a paradigm for TRM functioning as a self-sufficient first line of adaptive immunity.<\/jats:p>","DOI":"10.1084\/jem.20151916","type":"journal-article","created":{"date-parts":[[2016,7,4]],"date-time":"2016-07-04T10:12:22Z","timestamp":1467627142000},"page":"1571-1587","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":218,"title":["Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-7994","authenticated-orcid":false,"given":"Karin","family":"Steinbach","sequence":"first","affiliation":[{"name":"Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilena","family":"Vincenti","sequence":"additional","affiliation":[{"name":"Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0335-2733","authenticated-orcid":false,"given":"Mario","family":"Kreutzfeldt","sequence":"additional","affiliation":[{"name":"Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5845-6831","authenticated-orcid":false,"given":"Nicolas","family":"Page","sequence":"additional","affiliation":[{"name":"Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6870-1378","authenticated-orcid":false,"given":"Andreas","family":"Muschaweckh","sequence":"additional","affiliation":[{"name":"Klinikum rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, 81675 Munich, Germany 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Wagner","sequence":"additional","affiliation":[{"name":"Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6903-9144","authenticated-orcid":false,"given":"Ingo","family":"Drexler","sequence":"additional","affiliation":[{"name":"Institute of Virology, University Hospital D\u00fcsseldorf, Heinrich-Heine-University, 40225 D\u00fcsseldorf, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pinschewer","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University of Basel, 4056 Basel, Switzerland 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3633-0955","authenticated-orcid":false,"given":"Thomas","family":"Korn","sequence":"additional","affiliation":[{"name":"Klinikum rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, 81675 Munich, Germany 2"},{"name":"Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-2007","authenticated-orcid":false,"given":"Doron","family":"Merkler","sequence":"additional","affiliation":[{"name":"Departement de Pathologie et Immunologie, Centre Medical Universitaire, University of Geneva, 1211 Geneva, Switzerland 1"},{"name":"Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland 6"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,7,4]]},"reference":[{"key":"2023072603280772300_bib1","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1038\/nm.3962","article-title":"Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma","volume":"21","author":"Adachi","year":"2015","journal-title":"Nat. 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