In vivo imaging of lymphocytes in the CNS reveals different behaviour of naïve T cells in health and autoimmunity

Herz, Josephine; Paterka, Magdalena; Niesner, Raluca; Brandt, Alexander U.; Siffrin, Volker; Leuenberger, Tina; Birkenstock, Jérôme; Mossakowski, Agata A.; Glumm, Robert; Zipp, Frauke; Radbruch, Helena

doi:10.1186/1742-2094-8-131

Cited by 43 publications

(39 citation statements)

References 37 publications

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“…Therefore, this indicates a lack of local reactivation or local inflammatory signals in the CD8-only mice. Similar low-motility patterns were shown for nonactivated T cells that did not find adequate migratory signals in CNS tissue (39). In contrast, when CD4 + T cells were present, the clinical disease course of CD4 + CD8 mice in comparison with CD4-only mice was strongly disabling, yet similar in both groups, which indicates that the CD4 + T cells are the inducers of the clinical disease.…”

Section: Discussionsupporting

confidence: 62%

The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35–55–Induced Experimental Autoimmune Encephalomyelitis

Leuenberger

Paterka

Reuter

et al. 2013

The Journal of Immunology

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T cells have an essential role in the induction of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Although for CD4+ T cells it is well established that they contribute to the disease, less is known about the role of CD8+ T cells. Our aim was to determine the individual contribution of CD4+ and CD8+ T cells in myelin oligodendrocyte glycoprotein (MOG)35–55–induced EAE. We investigated MOG35–55–activated CD8+ T cells to clarify their potential to induce or attenuate EAE. We monitored the behavior of CD8+ T cells and their interaction with CD4+ T cells directly at the site of inflammation in the CNS using intravital imaging of the brainstem of EAE-affected living anesthetized mice. We found that mice without CD4+ T cells did not develop relevant clinical signs of disease, although CD8+ T cells were present in the CNS of these mice. These CD8+ T cells displayed reduced motility compared with those in the presence of CD4+ T cells. In mice that harbored CD4+ and CD8+ T cells, we saw a similar extent of clinical signs of EAE as in mice with only CD4+ T cells. Furthermore, the dynamic motility and viability of CD4+ T cells were not disturbed by CD8+ T cells in the lesions of these mice. Therefore, we conclude that in MOG35–55–induced EAE, CD8+ T cell accumulation in the CNS represents instead an epiphenomenon with no impact on clinical disease or on the effects of CD4+ T cells, the latter being the true inducers of the disease.

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Section: Discussionsupporting

confidence: 62%

The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35–55–Induced Experimental Autoimmune Encephalomyelitis

Leuenberger

Paterka

Reuter

et al. 2013

The Journal of Immunology

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“…A paradigmatic case of a superdiffusive walk is the Lévy walks characterized by a power–law move length probability distribution with finite speed and random turning directions between move lengths 87,88 . Lévy walks (and models alike 110 ) are effective at randomly solving the key tension between encountering nearby and faraway targets 85,87,88,95 , because they ensure a good local space-filling strategy and at the same time a superlinear overall spreading dynamics (superdiffusion) that reduces the time needed to reach distant areas. However, Lévy patterns could also emerge from informed movement and its interaction with the environment and not directly from an explorative process.…”

Section: Figurementioning

confidence: 99%

“…In the cortex of the inflamed CNS of mice with Experimental Autoimmune Encephalomyelitis (EAE) or during Toxoplasma gondii infection 94, 95 , effector T cells migrate on reticular structures of unknown composition. The parenchyma, however, supports effector auto-reactive T cells migration and interaction with phagocytic APCs during EAE without providing any obvious structures for guidance 96 .…”

Section: Introductionmentioning

confidence: 99%

T cell migration, search strategies and mechanisms

2016

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T cell migration is essential for T cell responses, allowing for detection of cognate antigen at the surface of an Antigen-Presenting Cell (APC) and for interactions with other cells involved in the immune response. Although appearing random, growing evidence supports that T cell motility patterns are strategic and governed by mechanisms that are optimized for both activation-stage and environment-specific attributes. In this Opinion Article, we will discuss how to understand the combined effects of T cell- intrinsic and -extrinsic forces upon these motility patterns when viewed in highly complex tissues filled with other cells involved in parallel motility. In particular, we will examine how insights from ‘search theory’ describe T cell movement across exploitation-exploration gradients, in the context of activation versus effector function and in the context of lymph nodes versus peripheral tissues.

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“…A total of 750 000 cells accurately reflects the number of circulating Tregs under physiologic conditions in rodents 23 and are in good accordance with other adoptive cell-transfer protocols in immunodeficient mice. 24 The increase of circulating Treg numbers induced a significant increase in stroke size on day 1 after 30 minutes of tMCAO (n ϭ 8, P Ͻ .05; Figure 3A). Thirty minutes of tMCAO is a well-accepted model of mild ischemic stroke, which under basal conditions causes infarctions of the deep basal ganglia but leaves the cortex intact.…”

Section: Adoptive Transfer Of Tregs Worsens Outcome After Ischemic Stmentioning

confidence: 99%

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Kleinschnitz

Kraft

Dreykluft

et al. 2013

Blood

308

293

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Key Points• Regulatory T cells are promoters of ischemic stroke by inducing dysfunction of the cerebral microvasculature. We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic antiinflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in IntroductionIschemic stroke induces a profound local inflammatory response involving various types of immune cells that transmigrate across the activated blood-brain barrier to invade the brain in a timed fashion. 1 Although previous research mainly focused on the role of innate immune cells, 2 recent evidence suggests that T cells, which belong to the adaptive immune system, also contribute critically to stroke development, especially in the early phase. 3 T cells have been identified in the postischemic brain as soon as 24 hours after reperfusion, 4 and Abs directed against vascular adhesion receptors expressed on the brain endothelium or leukocyte very late antigen-4 (VLA-4) expressed on lymphocytes inhibited T-cell transmigration and reduced tissue damage in models of stroke. 5 We and others showed recently that recombination activating gene (Rag1)-deficient mice, which lack functional T cells, are largely resistant against ischemic neurodegeneration. 6-8 T cellmediated brain damage became manifest by 24 hours after transient middle cerebral artery occlusion (tMCAO) and did not depend on antigen recognition or costimulation. 8 This clearly argues against TCR-driven mechanisms of tissue damage and suggests instead that T cells act detrimentally in ischemic stroke through antigenindependent pathways, at least during the early phase. Moreover, Rag1 Ϫ/Ϫ mice did not display a gross defect in thrombus formation after artificial vessel wall injury, which could easily explain the stroke protective phenotype in these animals. 8 Although the deleterious effects of T cells in stroke pathophysiology are well accepted, the functional relevance of the different T-cell subsets for stroke progression is less clear, as is their pathologic contribution at the different stages of cerebral ischemia (ie, acute versus chronic). Using adoptive cell transfer in Rag1 Ϫ/Ϫ mice, we could demonstrate that natural killer T cells (NKT cells) Submitted April 26, 2012; accepted October 27, 2012.Prepublished online as Blood First Edition paper, November 15, 2012; DOI 10.1182/blood-2012-04-426734. *C.K. and P.K. ...

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In vivo imaging of lymphocytes in the CNS reveals different behaviour of naïve T cells in health and autoimmunity

Cited by 43 publications

References 37 publications

The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35–55–Induced Experimental Autoimmune Encephalomyelitis

The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35–55–Induced Experimental Autoimmune Encephalomyelitis

T cell migration, search strategies and mechanisms

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

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