Antigen Dependently Activated Cluster of Differentiation 8-Positive T Cells Cause Perforin-Mediated Neurotoxicity in Experimental Stroke

Mracskó, Éva; Liesz, Arthur; Stojanović, Ana; Lou, Wilson Pak-Kin; Osswald, Matthias; Zhou, Wei; Karcher, Simone; Winkler, Frank; Martín-Villalba, Ana; Cerwenka, Adelheid; Veltkamp, Roland

doi:10.1523/jneurosci.1867-14.2014

Cited by 86 publications

(73 citation statements)

References 47 publications

(22 reference statements)

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“…To determine whether the exacerbation of such injury in GFAP-IL-15 tg mice is mediated by the impact of astrocytic IL-15 on CD8 + T and NK cells, we induced ischemia in WT and GFAP-IL-15 tg mice given anti-CD8 or -NK1.1 mAb 1 d before the induction of MCAO. As reported (32,36,37), CD8…”

Section: Impact Of Cd8 + T and Nk Cells On Ischemic Brain Injury In Gsupporting

confidence: 65%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

147

140

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Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) Infiltrating leukocytes such as lymphocytes are major effectors of postischemic brain inflammation (1-6). The phenotype and function of infiltrating lymphocytes are largely dictated by organspecific intrinsic factors during inflammatory responses (7-9), and such factors in the brain are unique in terms of cellular constituents, blood-brain barrier (10-12), and microenvironment (1-3, 7). As the most abundant cell type in the CNS, astrocytes constitute nearly 50% of the human brain's volume. Astrocytes contribute to the regulation of neural transmission, survival of neurons and other glia cells, and integrity of the blood-brain barrier. In the inflamed CNS, astrocytes engage in significant cross-talk with CNS-infiltrating immune cells by providing a major source of the proinflammatory cytokines and chemokines, thereby activating infiltrating lymphocytes. Evidence has shown that astrocytes can exert potent proinflammatory functions by producing factors including monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), etc., as their primary mode of action after CNS injury. In addition, astrocytes are considered as important nonprofessional antigen-presenting cells. Depending on the stage of brain pathology, astrocytes also possess antiinflammatory properties such as scar formation and restriction of inflammation by producing transforming growth factor-β (13,14). Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15-18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.IL-15 belongs to a family of cytokines using the common γ-chain as a component of their receptors (19,20). IL-15 interacts specifically with the high-affinity IL-15 receptor α (IL-15Rα) and binds to IL-2/IL-15Rβ and a common γ-chain expressed by target cells (21-23). In the periphery, monocytes and dendritic cells are the main sources of 25). IL-15 maintains homeostasis and cytotoxic activities of lymphocytes that bear its receptor [i.e., natural killer (NK) and CD8 + T cells] (19,20). Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major...

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Section: Impact Of Cd8 + T and Nk Cells On Ischemic Brain Injury In Gsupporting

confidence: 65%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

147

140

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“…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]. The dynamics of this deleterious role of different proinflammatory T cells have not been fully elucidated.…”

Section: Immune Mechanismsmentioning

confidence: 99%

Clinical Trials of Immunomodulation in Ischemic Stroke

Veltkamp

Gill

2016

Neurotherapeutics

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Inflammatory mechanisms are currently considered as a prime target for stroke therapy. There is evidence from animal studies that immune signals and mediators can have both detrimental and beneficial effects in particular stages of the disease process. Moreover, several of these mechanisms are turned on with sufficient delay after ischemia onset to make them amenable to therapeutic intervention. Several clinical proof-of concept trials have investigated the efficacy of different immunomodulatory approaches in patients with stroke. Trials targeting the innate immune system have focused on reduction of microglial activation, inhibition of neutrophil migration, and interleukin-1 receptor blockade, suggesting that interleukin-1 receptor blockade may be a promising strategy. Studies aiming at halting T-cell migration have also been undertaken with controversial findings regarding prevention of infarct growth in neuroimaging studies. Consistently, recent proof-of-concept trials targeting lymphocytes with drugs such as natalizumab and fingolimod have yielded some promising results on clinical endpoints, but confirmation in larger trials is needed. At present, the understanding of the role of immune mechanisms in neurorepair and neurodegeneration is limited. Improving long-term brain function by mitigating prolonged neuroinflammation that was triggered by acute brain injury could be a strategy in addition to neuroprotection.

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“…Although the majority of studies suggest that T cell populations are deleterious to ischemic stroke outcomes, several studies suggest a more nuanced interpretation of their role 125, 126 . Most studies have found that within the first 24h of ischemic injury, antigen-independent T-cells exert a deleterious effect; this is in contrast to antigen-dependent T-cell responses, which peak 3–7 days after the ischemic insult 127 . CD4+ T-cells are also likely to have deleterious effects, through the secretion of inflammatory cytokines including INF-γ and IL-21 127, 128 .…”

Section: Adaptive Immunity and Strokementioning

confidence: 99%

“…Most studies have found that within the first 24h of ischemic injury, antigen-independent T-cells exert a deleterious effect; this is in contrast to antigen-dependent T-cell responses, which peak 3–7 days after the ischemic insult 127 . CD4+ T-cells are also likely to have deleterious effects, through the secretion of inflammatory cytokines including INF-γ and IL-21 127, 128 . In contrast, CD8+T-cells, through the perforin-granzyme pathway, can cause neuronal cell death and may worsen stroke outcomes 127 .…”

Section: Adaptive Immunity and Strokementioning

confidence: 99%

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Inflammatory Disequilibrium in Stroke

Petrovic-Djergovic

Goonewardena

Pinsky

2016

Circulation Research

206

164

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Over the past several decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. Understanding the benefits of timely reperfusion has led to the development of thrombolytic therapy as the cornerstone of current management of ischemic stroke, but there remains much to be learned about mechanisms of neuronal ischemic and reperfusion injury and associated inflammation. For ischemic stroke, novel therapeutic targets have continued to remain elusive. When considering modern molecular biologic techniques, advanced translational stroke models, and clinical studies, a consistent pattern emerges, implicating perturbation of the immune equilibrium by stroke in both central nervous system injury and repair responses. Stroke triggers activation of the neuroimmune axis, comprised of multiple cellular constituents of the immune system resident within the parenchyma of the brain, leptomeninges, and vascular beds, as well as through secretion of biological response modifiers and recruitment of immune effector cells. This neuroimmune activation can directly impact the initiation, propagation, and resolution phases of ischemic brain injury. In order to leverage a potential opportunity to modulate local and systemic immune responses to favorably affect the stroke disease curve, it is necessary to expand our mechanistic understanding of the neuroimmune axis in ischemic stroke. This review explores the frontiers of current knowledge of innate and adaptive immune responses in the brain and how these responses together shape the course of ischemic stroke.

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Antigen Dependently Activated Cluster of Differentiation 8-Positive T Cells Cause Perforin-Mediated Neurotoxicity in Experimental Stroke

Cited by 86 publications

References 47 publications

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Clinical Trials of Immunomodulation in Ischemic Stroke

Inflammatory Disequilibrium in Stroke

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