Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Schneider‐Hohendorf, Tilman; Stenner, Max-Philipp; Weidenfeller, Christian; Zozulya, Alla L.; Simon, Ole J.; Schwab, Nicholas; Wiendl, Heinz

doi:10.1002/eji.201040558

Cited by 63 publications

(57 citation statements)

References 30 publications

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“…8 We recently showed that natural Tregs bear an intrinsic propensity for migration, thus increasing the probability of a Treg-endothelial cell interaction compared with non-Tregs. 34 In the present study, we extended these findings by demonstrating that Tregs are especially prone to adhere to the vascular endothelium via LFA-1/ICAM-1 binding under ischemic conditions, and blocking of this pathway abolished the stroke-enhancing activity of Tregs by reducing intravascular thrombosis and improving tissue reperfusion. Moreover, depletion of platelets also prevented Tregdriven infarct progression in Rag1 Ϫ/Ϫ mice.…”

supporting

confidence: 59%

“…Indeed, circulating natural CD4 ϩ CD25 ϩ Tregs expressed significantly higher amounts of LFA-1 than CD4 ϩ CD25 Ϫ non-Tregs on day 1 after tMCAO (n ϭ 6, P Ͻ .05; Figure 6A right), which confirms our previous data under nonischemic conditions. 34 Mechanistically, blocking of LFA-1 in CD4 ϩ CD25 ϩ -reconstituted Rag1 Ϫ/Ϫ mice Rag1 Ϫ/Ϫ mice were treated with antiplatelet serum to deplete circulating platelets or controls serum and infarct volumes were determined on day 1. Depletion of platelets reversed the stroke-enhancing effect of CD4 ϩ CD25 ϩ Tregs and also of CD4 ϩ CD25 Ϫ non-Tregs in Rag1 Ϫ/Ϫ mice.…”

Section: Regulatory T Cells Promote Stroke 685mentioning

confidence: 99%

“…Indeed, circulating natural CD4 ϩ CD25 ϩ Tregs expressed significantly higher amounts of LFA-1 than CD4 ϩ CD25 Ϫ non-Tregs on day 1 after tMCAO (n ϭ 6, P Ͻ .05; Figure 6A right), which confirms our previous data under nonischemic conditions. 34 Mechanistically, blocking of LFA-1 in CD4 ϩ CD25 ϩ -reconstituted Rag1 Ϫ/Ϫ mice Tregs or CD4 ϩ CD25 Ϫ non-Tregs were transferred into Rag1 Ϫ/Ϫ mice 24 hours before 60 minutes of tMCAO in the presence of anti-LFA-1 blocking Abs or control Abs. Infarct volumes were determined on day 1.…”

mentioning

confidence: 99%

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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

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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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supporting

confidence: 59%

Section: Regulatory T Cells Promote Stroke 685mentioning

confidence: 99%

“…Indeed, circulating natural CD4 ϩ CD25 ϩ Tregs expressed significantly higher amounts of LFA-1 than CD4 ϩ CD25 Ϫ non-Tregs on day 1 after tMCAO (n ϭ 6, P Ͻ .05; Figure 6A right), which confirms our previous data under nonischemic conditions. 34 Mechanistically, blocking of LFA-1 in CD4 ϩ CD25 ϩ -reconstituted Rag1 Ϫ/Ϫ mice Tregs or CD4 ϩ CD25 Ϫ non-Tregs were transferred into Rag1 Ϫ/Ϫ mice 24 hours before 60 minutes of tMCAO in the presence of anti-LFA-1 blocking Abs or control Abs. Infarct volumes were determined on day 1.…”

mentioning

confidence: 99%

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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

Self Cite

308

293

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“…A decrease or functional abnormality in Tregs can result in various autoimmune diseases. [9][10][11] Regarding heart failure, Tang, et al reported an association between peripheral Tregs and heart failure in HF patients who were stable on optimal therapy for at least 3 months.…”

Section: Cd4mentioning

confidence: 99%

Prognostic Value of Circulating Regulatory T Cells for Worsening Heart Failure in Heart Failure Patients With Reduced Ejection Fraction

et al. 2014

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SummaryRegulatory T cells (Tregs) play a crucial role in the negative regulation of immune responses. Recent studies suggest that Tregs are involved in the pathogenesis of atherosclerosis and myocarditis. Here, we investigated the involvement of Tregs on worsening heart failure (HF) in patients with reduced ejection fraction (HF-REF). The study population consisted of 32 HF-REF patients who were hospitalized for worsening HF, and 18 control subjects. Cardiac function was evaluated by echocardiography. A single venous blood sample was collected before discharge. Circulating T cells were evaluated by fl ow cytometry. Tregs were defi ned as CD4 Our data suggest that Tregs might be involved in the pathogenesis of decompensated HF, and may be a novel predictor of poor prognosis in HF-REF patients. (Int Heart J 2014; 55: 271-277)

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“…For flow cytometric analysis of immune cell infiltration in the CNS, mononuclear cells were isolated as previously described (48). Briefly, anesthetized mice were transcardially perfused with 20 mL of PBS, and CNS tissue was removed, homogenized with scissors, and digested with Collagenase Type IA (0.4 mg/mL; Sigma Aldrich) for 30 min in a water bath at 37°C.…”

Section: Methodsmentioning

confidence: 99%

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Klotz

Kuzmanov

Hucke

et al. 2016

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

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Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the bloodbrain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4 + T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immuneregulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.neuroinflammation | multiple sclerosis | spontaneous EAE | CNS lesion distribution | blood-brain barrier M ultiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Disease pathogenesis is initiated by peripheral activation of autoimmune T lymphocytes by yet unknown mechanisms, followed by T-cell expansion and subsequent migration across the complex structure of the blood-brain barrier (BBB). Within the CNS, entry of this first wave of T cells elicits recruitment of other immune cells, which together evoke a local inflammatory process ultimately resulting in demyelination, as well as axonal and neuronal damage (1). Several histological MS subtypes have been described with regard to lesion distribution and cellular composition (2). The reasons underlying distinct lesion development at different anatomical sites still remain however largely elusive: Some authors have proposed that the nature and expression pattern of the target autoantigen might play a role (3, 4). Others have observed an influence of the HLA complex and its role in shaping antigen presentation, thus suggesting that T-cell antigen specificity might impact the location of inflammation (5). Additionally, T-cell polarization into distinct T helper subtypes, as well as their expression pattern of chemokine receptors and adhesion molecules, has been implicated in determining the lo...

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Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Cited by 63 publications

References 30 publications

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

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

Prognostic Value of Circulating Regulatory T Cells for Worsening Heart Failure in Heart Failure Patients With Reduced Ejection Fraction

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

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