Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE

Rothhammer, Veit; Heink, Sylvia; Petermann, Franziska; Srivastava, Rajneesh; Claussen, Malte Christian; Hemmer, Bernhard; Korn, Thomas

doi:10.1084/jem.20110434

Cited by 231 publications

(281 citation statements)

References 67 publications

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“…The blockade of VLA-4 did not block Th17 cells to infiltrate the brain, expressing both IL-23R and CCR6. Accordingly, T cell-conditional 4-deficient mice were not resistant to actively induced EAE but showed an ataxic syndrome with predominantly supraspinal infiltrates of T cells (Rothhammer V 2011). Corroborating this idea, it was previously showed that Th17 cells constitutively express the chemokine receptor CCR6, whose ligand, CCL20 is also constitutively expressed by choroid plexus cells.…”

Section: Self-tolerancementioning

confidence: 94%

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

Peron¹,

Oliveira²,

Brandão³

et al. 2012

Autoimmune Diseases - Contributing Factors, Specific Cases of Autoimmune Diseases, and Stem Cell and Other Therapies

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Section: Self-tolerancementioning

confidence: 94%

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

Peron¹,

Oliveira²,

Brandão³

et al. 2012

Autoimmune Diseases - Contributing Factors, Specific Cases of Autoimmune Diseases, and Stem Cell and Other Therapies

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“…While Th1 cells critically rely on α4-integrins, Th17 cells can cross the brain barriers in an α4-integrin-independent manner and enter the CNS [22,23]. We next investigated if presence or absence of PSGL-1 has any influence in the polarization of our PLP-specific T-cell lines into Th1, Th17, or Th2 cells.…”

Section: Establishment Of Effector Memory Wt and Psgl-1 −/− Sjl/j T-cmentioning

confidence: 99%

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

et al. 2014

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T-cell migration across the blood-brain barrier is a crucial step in the pathogenesis of EAE, an animal model for MS. Live cell imaging studies demonstrated that P-selectin glycoprotein ligand-1 (PSGL-1) and its endothelial ligands E-and P-selectin mediate the initial rolling of T cells in brain vessels during EAE. As functional absence of PSGL-1 or E/P-selectins does not result in ameliorated EAE, we speculated that T-cell entry into the spinal cord is independent of PSGL-1 and E/P-selectin. Performing intravital microscopy, we observed the interaction of WT or PSGL-1 −/− proteolipid protein-specific T cells in inflamed spinal cord microvessels of WT or E/P-selectin −/− SJL/J mice during EAE. T-cell rolling but not T-cell capture was completely abrogated in the absence of either PSGL-1 or E-and P-selectin, resulting in a significantly reduced number of T cells able to firmly adhere in the inflamed spinal cord microvessels, but did not lead to reduced T-cell invasion into the CNS parenchyma. Thus, PSGL-1 interaction with E/P-selectin is essential for T-cell rolling in inflamed spinal cord microvessels during EAE. Taken together with previous observations, our findings show that T-cell rolling is not required for successful T-cell entry into the CNS and initiation of EAE.Keywords: Blood-brain barrier r Experimental autoimmune encephalomyelitis r P-selectin r P-selectin glycoprotein ligand-1 r T-cell rolling Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn MS, and in its animal model, EAE, neuro-Ag-specific CD4 + (where CD is cluster of differentiation) T cells breach the bloodbrain barrier (BBB) and gain access to the CNS, where they cause inflammation, demyelination, and BBB breakdown leading to the clinical manifestation of these diseases. T-cell migration across the BBB is a multi-step process mediated by the sequential interaction of different adhesion and/or signaling molecules on the T cells and Correspondence: Prof. Britta Engelhardt e-mail: bengel@tki.unibe.ch the highly specialized endothelium of the BBB [1]. The discovery that α4β1-integrin plays a critical role in T-cell trafficking across the BBB during EAE has led to the development of a humanized monoclonal anti-α4-integrin Ab (natalizumab) for the treatment of MS [2].In vivo live cell imaging studies have provided direct evidence that the multistep extravasation of encephalitogenic T cells across the spinal cord microvasculature during initiation of EAE is unique [3]. Initiation of T-cell interaction with the spinal cord microvascular endothelium takes place in the absence of rolling and is rather mediated by α4-integrin-mediated G-protein-independent capture and subsequent G-protein-dependent arrest of the T cells in spinal cord microvessels [3]. Once neuroinflammation iswww.eji-journal.eu 2288 Karthik Sathiyanadan et al. Eur. J. Immunol. 2014. 44: 2287-2294 ongoing, it is mostly T-cell rolling with a few alternative capture events also detected, which characterize th...

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“…It has been previously shown that IVIg interferes with leukocyte recruitment to the CNS in an a4 integrin-dependent manner (24). However, Th17 and Th1 cells use different strategies to invade the CNS (25,26). To investigate the effect of IVIg on trafficking of Th17 and Th1 in EAE, brain and spinal cords were analyzed on the day of onset (day 9).…”

Section: Ivig Decreases Infiltration Of Lymphocytes To the Cns By Inhmentioning

confidence: 99%

Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

Othy

Hegde

Topçu

et al. 2013

The Journal of Immunology

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Despite an increasing use of high-dose therapy of i.v. gammaglobulin (IVIg) in the treatment of various T cell– and Ab-mediated inflammatory and autoimmune diseases, comprehension of the mechanisms underlying its therapeutic benefit has remained a major challenge. Particularly, the effect of IVIg in T cell–mediated autoimmune conditions remains unexplored. Using an actively induced experimental autoimmune encephalomyelitis model, a T cell–mediated autoimmune condition, we demonstrate that IVIg inhibits the differentiation of naive CD4 T cells into encephalitogenic subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3+ regulatory T cells. Further, IVIg renders effector T cells less pathogenic by decreasing the expression of encephalitogenic molecular players like GM-CSF and podoplanin. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB is dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Additionally, F(ab′)2 fragments also retained this function of IVIg. IVIg or F(ab′)2 fragments decrease the sphingosine-1 phosphate receptor on CD4 cells, thus sequestering these cells in the draining lymph nodes and decreasing their infiltration into the CNS. Our study reveals a novel role of Igs in the modulation of polarization and trafficking of T lymphocytes, accounting for the observed beneficial effect in IVIg therapy.

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Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE

Abstract: Th1 lymphocytes preferentially infiltrate into the spinal cord during EAE via a VLA-4–mediated mechanism while Th17 lymphocyte infiltration is dependent on LFA-1 expression.

Cited by 231 publications

References 67 publications

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

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