The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of ␣␤ and ␥␦ T cells in a murine model of stroke and distinguished 2 different T cell-dependent proinflammatory pathways in ischemiareperfusion injury. IFN-␥ produced by IntroductionIschemic stroke represents a major cause of disability and death in the western world. 1 Although infiltration of inflammatory leukocytes is a well-described feature of human stroke, 2 the perspective that activation of the immune systems is a bystander phenomenon secondary to ischemic tissue damage has changed. Currently, the activation of the immune system is recognized as a major element in all stages of the pathophysiology of stroke, including long lasting regenerative processes. 1,3 Release of danger molecules, local expression of proinflammatory cytokines, the subsequent expression of endothelial adhesion molecules, and breakdown of the blood-brain barrier are among the initial events after arterial occlusion. 3 These events are followed by an amplification of the postischemic inflammation that involves both resident brain cells and infiltrating immune cells. With the use of a mouse model of middle cerebral artery occlusion (MCAO), our group has previously shown a sequentially organized accumulation of immune cells of both the innate and adaptive immune systems in the ischemic brain. 4 The cellular infiltrate is dominated by neutrophils, macrophages, and microglia, but also includes T, natural killer, and dendritic cells.At this early stage, different T-cell subpopulations play important roles even if their absolute abundance in the ischemic brain is low. CD4 ϩ and CD8 ϩ T cells, as well as ␥␦ T cells, promote further tissue damage, 5-8 whereas regulatory T cells and B cells are protective. 9,10 Cytokines involved in the proinflammatory response include IL-1␤, IL-12, and IL-23, as well as interferon ␥ (IFN-␥), IL-17A, and TNF-␣. In contrast IL-4, TGF-␤, and mostly IL-10 are part of protective pathways. 9,11,12 However, the specific integration of each cell type and cytokine in the postischemic inflammatory network still has to be elucidated.In sterile inflammations, including ischemia, IL-17A can be crucial for chemokine induction. 13,14 Importantly, IL-17A can be rapidly released by ␥␦ T cells in response to cytokine activation or engagement of innate receptors, in the absence of TCR activation. 15 Beside IL-17A, IFN-␥ pathways are also implicated in ischemia/reperfusion (I/R) injury. 13,16 In autoimmunity, IFN-␥ production is associated with induction of MHCII expression, production of chemokines, and activation of macrophages. 17 Our analysis of the evolving local and systemic inflammatory responses after stroke has yielded 2 new distinct and crosslinked pathways: First, IFN-␥ produced by ␣␤ T cells induces the expression of TNF-␣ in macrophages. Second, ␥␦ T cells lead to neutrophil infiltration via the IL-1...

Our results suggest a central role for interferon regulatory factor 4-positive IL-23-producing conventional DCs in the IL-17-dependent secondary tissue damage in stroke.

Multi-parametric MRI distinguishes two subtypes of PACNS that most likely differ concerning the affected vessel size. Biopsy-proven PACNS primarily involves smaller vessels beyond the resolution of vascular imaging, while imaging-based PACNS affects predominantly medium-sized vessels leading to false-negative biopsy results. Using distinct MRI patterns may be helpful for selecting patients for appropriate invasive diagnostic modalities.