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...

T cells recruited to the kidney contribute to tissue damage in crescentic and proliferative glomerulonephritides. Chemokines and their receptors regulate T cell trafficking, but the expression profile and functional importance of chemokine receptors for renal CD4 ϩ T cell subsets are incompletely understood. In this study, we observed that renal

Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. The chemokine receptor CXCR3 is highly expressed on Th1 cells and is supposed to be crucial for their trafficking into inflamed tissues. In this study, we explored the functional role of CXCR3 using the MRL/MpJ-Faslpr (MRL/lpr) mouse model of systemic lupus erythematosus that closely resembles the human disease. CXCR3−/− mice were generated and backcrossed into the MRL/lpr background. Analysis of 20-wk-old CXCR3−/− MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment. Most importantly, not only the numbers of renal IFN-γ-producing Th1 cells, but also of IL-17-producing Th17 cells were significantly reduced. Unlike in inflamed kidneys, there was no reduction in the numbers of IFN-γ- or IL-17-producing T cells in spleens, lymph nodes, or the small intestine of MRL/lpr CXCR3−/− mice. This observation suggests impaired trafficking of effector T cells to injured target organs, rather than the inability of CXCR3−/− mice to mount efficient Th1 and Th17 immune responses. These findings show a crucial role for CXCR3 in the development of experimental lupus nephritis by directing pathogenic effector T cells into the kidney. For the first time, we demonstrate a beneficial effect of CXCR3 deficiency through attenuation of both the Th1 and the newly defined Th17 immune response. Our data therefore identify the chemokine receptor CXCR3 as a promising therapeutic target in lupus nephritis.

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice.