title: Antigen dependently activated cluster of differentiation 8-positive T cells cause perforin-mediated neurotoxicity in experimental stroke.
abstract: Neuroinflammation plays a key role in secondary brain damage after stroke. Although deleterious effects of proinflammatory cytokines are well characterized, direct cytotoxic effects of invading immune cells on the ischemic brain and the importance of their antigen-dependent activation are essentially unknown. Here we examined the effects of adaptive and innate immune cells-cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells-that share the direct perforin-mediated cytotoxic pathway on outcome after cerebral ischemia in mice. Although CTLs and NK cells both invaded the ischemic brain, only brain-infiltrating CTLs but not NK cells were more activated than their splenic counterparts. Depletion of CTLs decreased infarct volumes and behavioral deficit in two ischemia models, whereas NK cell depletion had no effect. Correspondingly, adoptive CTL transfer from wild-type into Rag1 knock-out mice increased infarct size. Adoptive CTL transfer from perforin knock-out or interferon-γ knock-out mice into Rag1 knock-out mice revealed that CTL neurotoxicity was mediated by perforin. Accordingly, CTLs isolated from wild-type or interferon-γ knock-out but not from perforin knock-out mice induced neuronal cell death in vitro. CTLs derived from ovalbumin-specific T-cell receptor transgenic mice were not activated and infiltrated less into the ischemic brain compared with wild-type CTLs. Their transfer did not increase the infarct size of Rag1 knock-out mice, indicating antigen-dependent activation as an essential component of CTL neurotoxicity. Our findings underscore the importance of antigen-dependent, direct cytotoxic immune responses in stroke and suggest modulation of CTLs and their effector pathways as a potential new strategy for stroke therapy.
authors.affiliation: Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Mracsko
authors.affiliation: Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany, Institute for Stroke and Dementia Research, Munich University Hospital, D-81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), D-80336 Munich, Germany, Groups.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
authors.affiliation: Innate Immunity and.
authors.forename: Ana
authors.initials: A
authors.lastname: Stojanovic
authors.affiliation: Molecular Neurobiology and.
authors.forename: Wilson Pak-Kin
authors.initials: WP
authors.lastname: Lou
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center, D-69120 Heidelberg, Germany, Department of Neurooncology at the National Center for Tumor Diseases, University Hospital Heidelberg, D-69120 Heidelberg, Germany, and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Osswald
authors.affiliation: Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Karcher
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center, D-69120 Heidelberg, Germany, Department of Neurooncology at the National Center for Tumor Diseases, University Hospital Heidelberg, D-69120 Heidelberg, Germany, and.
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
authors.affiliation: Molecular Neurobiology and.
authors.forename: Ana
authors.initials: A
authors.lastname: Martin-Villalba
authors.affiliation: Innate Immunity and.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
authors.affiliation: Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany, Division of Brain Sciences, Imperial College London, SW7 2AZ London, United Kingdom Roland.Veltkamp@med.uni-heidelberg.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003603:Cytotoxins / Q000633:toxicity*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin / Q000633:toxicity*; D020521:Stroke / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D003603:Cytotoxins; D054353:Perforin
keywords: NK cells; cytotoxic T lymphocytes; ischemic stroke; perforin