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(Circulation. 2006;113:2105-2112.)
© 2006 American Heart Association, Inc.

Stroke

Role of T Lymphocytes and Interferon- in Ischemic Stroke

Gokhan Yilmaz, MD^*; Thiruma V. Arumugam, PhD^*; Karen Y. Stokes, PhD; D. Neil Granger, PhD

From the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport.

Correspondence to D. Neil Granger, PhD, Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130-3932. E-mail dgrang{at}lsuhsc.edu

Received October 4, 2005; revision received January 11, 2006; accepted March 1, 2006.

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- (IFN-) 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- 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-. 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-^–/– 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-^–/– 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- plays a pivotal role in stroke-induced inflammatory responses, T lymphocytes appear to be a minor source of this cytokine.

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