Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation.
T cells contribute to the pathophysiology of ischemic stroke by yet unknown mechanisms. Mice with transgenic T-cell receptors (TCRs) and mutations in costimulatory molecules were used to define the minimal immunologic requirements for T cell-mediated ischemic brain damage. Stroke was induced in recombination activating gene 1-deficient (RAG1(-/-)) mice devoid of T and B cells, RAG1(-/-) mice reconstituted with B cells or T cells, TCR-transgenic mice bearing 1 single CD8(+) (2C/RAG2, OTI/RAG1 mice) or CD4(+) (OTII/RAG1, 2D2/RAG1 mice) TCR, mice lacking accessory molecules of TCR stimulation (CD28(-/-), PD1(-/-), B7-H1(-/-) mice), or mice deficient in nonclassical T cells (natural killer T [NKT] and gammadelta T cells) by transient middle cerebral artery occlusion (tMCAO). Stroke outcome was assessed at day 1. RAG1(-/-) mice and RAG1(-/-) mice reconstituted with B cells developed significantly smaller brain infarctions compared with controls, but thrombus formation after FeCl(3)-induced vessel injury was unimpaired. In contrast, TCR-transgenic mice and mice lacking costimulatory TCR signals were fully susceptible to tMCAO similar to mice lacking NKT and gammadelta T cells. These findings were corroborated by adoptive transfer experiments. Our data demonstrate that T cells critically contribute to cerebral ischemia, but their detrimental effect neither depends on antigen recognition nor TCR costimulation or thrombus formation.
Kleinschnitz
Christoph
C
Department of Neurology, University of Wuerzburg, D-97080 Wuerzburg, Germany. christoph.kleinschnitz@mail.uni-wuerzburg.de
Schwab
Nicholas
N
Kraft
Peter
P
Hagedorn
Ina
I
Dreykluft
Angela
A
Schwarz
Tobias
T
Austinat
Madeleine
M
Nieswandt
Bernhard
B
Wiendl
Heinz
H
Stoll
Guido
G
D056704:Adaptive Immunity; D000818:Animals; D055610:Antigens, CD1d / Q000502:physiology; D002545:Brain Ischemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018106:CD28 Antigens / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D016654:Genes, RAG-1 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D020521:Stroke / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013927:Thrombosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D055610:Antigens, CD1d; D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta