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.

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

“…Hurn et al (2007) reported that male SCID (severe combined immunodeficient) mice (deficient in both T and B cells), developed an B40% smaller infarct volume after 90 minutes focal ischemia and 22 hours reperfusion compared with wild-type mice. Two further studies similarly found B60% to 70% smaller infarct volumes as well as improved functional outcomes at 24 to 72 hours in recombinase activating gene-deficient (Rag1 À/À ) mice, which also lack T and B lymphocytes (Kleinschnitz et al, 2010b;Yilmaz et al, 2006). Moreover, there is good evidence that this protection of lymphocyte-deficient mice following stroke is due to the lack of T cells, and not B cells, as the reconstitution of B cells does not alter the protection observed in the Rag1 À/À mice.…”

Clinical Trials of Immunomodulation in Ischemic Stroke

“…A substantial role for the adaptive immune response after stroke is increasingly recognized. Transgenic animals deficient in lymphocytes consistently have smaller infarcts in different stroke models [23][24][25][26]. Moreover, antibody-mediated depletion of CD4 + , CD8 + , and γδ T cells reduced infarct volume and improved functional outcome [25,[27][28][29].…”

Stroke-Induced Immunodepression

“…For example, it has been demonstrated that T lymphocytes and IFN␥ contribute to the inflammatory and thrombogenic brain injury that results from cerebral ischemia. 12 Therefore, depletion of circulating T-cell populations and suppression of IFN␥ expression, which is the key mechanisms of strokeinduced immunodepression, might counteract the inflammatory brain after stroke. 7 Indeed, recent evidence from our laboratory indicates that stroke-induced immunodepression suppresses autoaggressive Th1 responses.…”