Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation

Abstract

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 γδ 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 γδ 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. © 2010 by The American Society of Hematology.