Cutting Edge: Loss of α4 Integrin Expression Differentially Affects the Homing of Th1 and Th17 Cells

Glatigny, Simon; Duhen, Rebekka; Oukka, Mohamed; Bettelli, Estelle

doi:10.4049/jimmunol.1102515

Cited by 72 publications

(81 citation statements)

References 19 publications

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“…The chemokine CCL19 is constitutively expressed on BBB endothelium and was proposed to mediate infiltration of chemokine (C-C motif) receptor 7 (CCR7) + T cells into the CNS [19,20]. Both our WT and PSGL-1 −/− T-cell lines did not bind a CCL19 Ig fusion protein, confirming that our T cells were CCR7 neg effector/memory T cells [21].Differentiation of CD4 + T helper cells into either Th1 or Th17 cells was shown to influence the molecular mechanisms these T-cell subsets use to enter the CNS during EAE [22]. 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].…”

mentioning

confidence: 72%

“…Differentiation of CD4 + T helper cells into either Th1 or Th17 cells was shown to influence the molecular mechanisms these T-cell subsets use to enter the CNS during EAE [22]. 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].…”

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

confidence: 99%

“…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%

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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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mentioning

confidence: 72%

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

confidence: 99%

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

confidence: 99%

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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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“…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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“…5H and I; Table 1) differed between Mx1.Cre + α 4‐integrin fl/fl mice and C57BL/6 control mice treated in vivo with poly I:C. Interestingly, we detected a preponderance of midbrain lesions in Mx1.Cre + α 4‐integrin fl/fl mice treated with poly I:C compared with controls, although this assessment was not quantitative. This observation may suggest a preferential migration into these anatomical locations by lymphocyte subsets that have a diminished requirement for α 4‐integrin to cross the BBB 32, 33, 34…”

Section: Resultsmentioning

confidence: 99%

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Hussain

Cravens

Doelger

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

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Cutting Edge: Loss of α4 Integrin Expression Differentially Affects the Homing of Th1 and Th17 Cells

Cited by 72 publications

References 19 publications

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

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

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

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