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Visualizing CD4 T-cell migration into inflamed skin and its inhibition by CCR4/CCR10 blockades using in vivo imaging model.

ABSTRACT: Chemokines are critical mediators of T-cell homing into inflamed skin. The complex nature of this multicellular response makes it difficult to analyse mechanisms mediating the early responses in vivo.To visualize directly T-cell homing into inflamed skin and its inhibition by blockades using a unique noninvasive confocal microscopy.A mouse model of allergic contact dermatitis was used. T cells from oxazolone-sensitized and -challenged Balb/c mice were first analysed phenotypically in vitro. CD4 T cells were then labelled with a tracker dye and transferred into Balb/c-SCID mice. The recipient mice were challenged with oxazolone and CD4 T-cell homing into inflamed skin was visualized.T cells with the skin homing receptors CCR4 and CCR10 were increased in the affected skin and draining lymph nodes, and effectively attracted by their specific chemokines CCL17, CCL22 and CCL27 in vitro. Using in vivo imaging, T-cell migration into the inflamed skin was observed at 2 h after application, peaking at 12 h and continuing for 48 h. Simultaneous systemic administration of neutralizing antibodies against CCR4 ligands (CCL17 and CCL22) and CCR10 ligand (CCL27) led to a significant suppression of T-cell migration and skin inflammation.Our data indicate that these tissue-selective adhesion molecules and chemokine/receptor pathways act in concert to attract specialized T-cell populations to mediate cutaneous inflammation. The in vivo imaging technique can be applicable to other models of cutaneous diseases to help with better understanding of the pathogenesis and monitoring the therapeutic effects.

SUBMITTER: Wang X

PROVIDER: S-EPMC3037861 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Visualizing CD4 T-cell migration into inflamed skin and its inhibition by CCR4/CCR10 blockades using in vivo imaging model.

Wang X X Fujita M M Prado R R Tousson A A Hsu H-C HC Schottelius A A Kelly D R DR Yang P A PA Wu Q Q Chen J J Xu H H Elmets C A CA Mountz J D JD Edwards C K CK

The British journal of dermatology 20091015 3

<h4>Background</h4>Chemokines are critical mediators of T-cell homing into inflamed skin. The complex nature of this multicellular response makes it difficult to analyse mechanisms mediating the early responses in vivo.<h4>Objectives</h4>To visualize directly T-cell homing into inflamed skin and its inhibition by blockades using a unique noninvasive confocal microscopy.<h4>Materials and methods</h4>A mouse model of allergic contact dermatitis was used. T cells from oxazolone-sensitized and -chal ...[more]

PMID: 19832835

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Project description:The extracellular matrix (ECM) is extensively remodeled during inflammation providing essential guidance cues for immune cell migration and signals for cell activation and survival. There is increasing interest in the therapeutic targeting of ECM to mitigate chronic inflammatory diseases and enhance access to the tumor microenvironment. T cells utilize the ECM as a scaffold for interstitial migration, dependent on T cell expression of matrix-binding integrins ?V?1/?V?3 and tissue display of the respective RGD-containing ligands. The specific ECM components that control T cell migration are unclear. Fibronectin (FN), a canonical RGD-containing matrix component, is heavily upregulated in inflamed tissues and in vitro can serve as a substrate for leukocyte migration. However, limited by lack of tools to intravitally visualize and manipulate FN, the specific role of FN in effector T cell migration in vivo is unknown. Here, we utilize fluorescently-tagged FN to probe for FN deposition, and intravital multiphoton microscopy to visualize T cell migration relative to FN in the inflamed ear dermis. Th1 cells were found to migrate along FN fibers, with T cells appearing to actively push or pull against flexible FN fibers. To determine the importance of T cell interactions with FN, we used a specific inhibitor of FN polymerization, pUR4. Intradermal delivery of pUR4 (but not the control peptide) to the inflamed skin resulted in a local reduction in FN deposition. We also saw a striking attenuation of Th1 effector T cell movement at the pUR4 injection site, suggesting FN plays a key role in T cell interstitial migration. In mechanistic studies, pUR4 incubation with FN in vitro resulted in enhanced tethering of T cells to FN matrix, limiting productive migration. In vivo, such tethering led to increased Th1 accumulation in the inflamed dermis. Enhanced Th1 accumulation exacerbated inflammation with increased Th1 activation and IFN? cytokine production. Thus, our studies highlight the importance of ECM FN fibrils for T cell migration in inflamed tissues and suggest that manipulating local levels of ECM FN may prove beneficial in promoting T cell accumulation in tissues and enhancing local immunity to infection or cancer.

Dataset Information

Visualizing CD4 T-cell migration into inflamed skin and its inhibition by CCR4/CCR10 blockades using in vivo imaging model.

Publications

Visualizing CD4 T-cell migration into inflamed skin and its inhibition by CCR4/CCR10 blockades using in vivo imaging model.

Similar Datasets

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