Role of T Lymphocytes and Interferon-γ in Ischemic Stroke

Abstract

Background— Although lymphocyte recruitment and activation are associated with cerebral ischemia-reperfusion (I/R) injury, the contributions of specific lymphocyte subpopulations and lymphocyte-derived interferon-γ (IFN-γ) to stroke remain unknown. The objectives of this study were to define the contribution of specific populations of lymphocytes to the inflammatory and prothrombogenic responses elicited in the cerebral microvasculature by I/R and to investigate the role of T-cell–associated IFN-γ in the pathogenesis of ischemic stroke. Methods and Results— Middle cerebral artery occlusion was induced for 1 hour (followed by 4 or 24 hours of reperfusion) in wild-type mice and mice deficient in lymphocytes (Rag1 −/− ), CD4 + T cells, CD8 + T cells, B cells, or IFN-γ. Platelet and leukocyte adhesion was assessed in cortical venules with intravital video microscopy. Neurological deficit and infarct volume were determined 24 hours after reperfusion. Rag1 −/− , CD4 + T-cell −/− , CD8 + T-cell −/− , and IFN-γ −/− mice exhibited comparable significant reductions in I/R-induced leukocyte and platelet adhesion compared with wild-type mice exposed to I/R. Infarct volume was reduced and I/R-induced neurological deficit was improved in immunodeficient Rag1 −/− mice. These protective responses were reversed in Rag1 −/− mice reconstituted with either wild-type or, to a lesser extent, IFN-γ −/− splenocytes. B-cell–deficient mice failed to show improvement against ischemic stroke injury. Conclusions— These findings indicate that CD4 + and CD8 + T lymphocytes, but not B lymphocytes, contribute to the inflammatory and thrombogenic responses, brain injury, and neurological deficit associated with experimental stroke. Although IFN-γ plays a pivotal role in stroke-induced inflammatory responses, T lymphocytes appear to be a minor source of this cytokine.