Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis

Alt, Carsten; Laschinger, Melanie; Engelhardt, Britta

doi:10.1002/1521-4141(200208)32:8<2133::aid-immu2133>3.0.co;2-w

Cited by 192 publications

(134 citation statements)

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“…Based on these findings, we hypothesized that these chemokines regulate not only the migration of pathogenic T cells into the CNS, which was suggested previously (9), but also the induction of pathogenic T cells. In the present study, we examined the role of the CCL19 and CCL21 chemokines in the induction of EAE using plt/plt mice.…”

supporting

confidence: 59%

“…The difference in immunizing protocols also might be an explanation. Repeated immunization of plt/plt mice may increase production of IL-6 and TGF-␤, thereby contributing to further generation of Th17 cells and development of EAE (9,11,12). Alternatively, stimulation with CXCL9, CXCL10, and/or CXCL11 via CXCR3, an additional receptor for mouse CCL21 (25)(26)(27), might partially substitute for CCR7 stimulation in heavily immunized plt/plt or CCR7 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…That EAE did not develop in plt/plt mice might be due to the failure of pathogenic T cells to migrate into the CNS because of the lack of CCR7 ligand expression, as suggested previously (9). To examine this possibility, 9 days after s.c. immunization, DLN cells from WT mice were incubated for 3 days with MOG peptide and then CD4 ϩ T cells were adoptively transferred i.v.…”

Section: Plt/plt Mice Lacking Expression Of Ccl19 and Ccl21 Are Resismentioning

confidence: 92%

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CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

Kuwabara¹,

Ishikawa²,

Yasuda³

et al. 2009

The Journal of Immunology

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CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG35–55-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-β were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG35–55-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.

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supporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Plt/plt Mice Lacking Expression Of Ccl19 and Ccl21 Are Resismentioning

confidence: 92%

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CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

Kuwabara¹,

Ishikawa²,

Yasuda³

et al. 2009

The Journal of Immunology

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“…1A). 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].…”

mentioning

confidence: 60%

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

Self Cite

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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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“…Remarkably, CCL21 released from lymphatic endothelial cells also promotes a directed growth of melanoma cells towards the lymphatics (Emmett et al, 2011). Interestingly, under inflammatory conditions, CCL19 and CCL21 were found to be up-regulated in endothelial cells of the blood-brain barrier (Alt et al, 2002) enabling acute T cell leukemia cells to infiltrate into the central nervous system in a CCR7-dependent manner (Buonamici et al, 2009). Furthermore, CCR7 also contributes to tumor cell survival by activating the PI3K/Akt signaling pathway (Wang et al, 2005).…”

Section: Biological Functionsmentioning

confidence: 99%

CCR7: Roles in cancer cell dissemination, migration and metastasis formation

Legler

Allmen

Hauser

2014

The International Journal of Biochemistry & Cell Biology

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Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis

Cited by 192 publications

References 45 publications

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

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

CCR7: Roles in cancer cell dissemination, migration and metastasis formation

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