Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Doebis, Cornelia; Siegmund, Kerstin; Loddenkemper, Christoph; Lowe, John B.; Issekutz, Andrew C.; Hamann, Alf; Huehn, Jochen; Syrbe, Uta

doi:10.2353/ajpath.2008.080052

Cited by 19 publications

(24 citation statements)

References 39 publications

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“…This seems particularly important for CD4 + TEM, which constitute a migratory pool of cells, whereas CD8 + memory T cells rather build up a pool of tissue-resident cells, for instance in the skin (48), suggesting cooperation of both subsets in secondary responses by different means. The expression of selectin ligands, which is particularly stable on in vivo-generated TEM (4), can support the proinflammatory function of CD4 + TEM in cutaneous inflammation (49). Alternatively, fut7 expression is also crucial in skin-specific T regulatory cells as they maintain skin tolerance and therefore require selectin-dependent entry into skin sites for in vivo suppression of peripheral inflammation (50-52).…”

Section: Discussionmentioning

confidence: 99%

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Pink

Ratsch

Mardahl

et al. 2016

The Journal of Immunology

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E- and P-selectin ligands (E- and P-ligs) guide effector memory T cells into skin and inflamed regions, mediate the inflammatory recruitment of leukocytes, and contribute to the localization of hematopoietic precursor cells. A better understanding of their molecular regulation is therefore of significant interest with regard to therapeutic approaches targeting these pathways. In this study, we examined the transcriptional regulation of fucosyltransferase 7 (FUT7), an enzyme crucial for generation of the glycosylated E- and P-ligs. We found that high expression of the coding gene fut7 in murine CD4+ T cells correlates with DNA demethylation within a minimal promoter in skin/inflammation-seeking effector memory T cells. Retinoic acid, a known inducer of the gut-homing phenotype, abrogated the activation-induced demethylation of this region, which contains a cAMP responsive element. Methylation of the promoter or mutation of the cAMP responsive element abolished promoter activity and the binding of CREB, confirming the importance of this region and of its demethylation for fut7 transcription in T cells. Furthermore, studies on human CD4+ effector memory T cells confirmed demethylation within FUT7 corresponding to high FUT7 expression. Monocytes showed an even more extensive demethylation of the FUT7 gene whereas hepatocytes, which lack selectin ligand expression, exhibited extensive methylation. In conclusion, we show that DNA demethylation within the fut7 gene controls selectin ligand expression in mice and humans, including the inducible topographic commitment of T cells for skin and inflamed sites.

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Section: Discussionmentioning

confidence: 99%

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Pink

Ratsch

Mardahl

et al. 2016

The Journal of Immunology

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“…Adhesion molecules expressed by leukocytes and endothelial cells play central roles in mediating this leukocyte recruitment (5)(6)(7)(8)(9)(10). Circulating leukocytes initiate contact with the endothelial surface via the processes of tethering and rolling, interactions predominantly dependent on the selectin family of adhesion molecules.…”

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confidence: 99%

Regulatory T Cells Dynamically Regulate Selectin Ligand Function during Multiple Challenge Contact Hypersensitivity

Abeynaike

Deane

Westhorpe

et al. 2014

The Journal of Immunology

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Regulatory T cells (Tregs) play critical roles in restricting T cell–mediated inflammation. In the skin, this is dependent on expression of selectin ligands required for leukocyte rolling in dermal microvessels. However, whether there are differences in the molecules used by Tregs and proinflammatory T cells to undergo rolling in the skin remains unclear. In this study, we used spinning disk confocal microscopy in Foxp3-GFP mice to visualize rolling of endogenous Tregs in dermal postcapillary venules. Tregs underwent consistent but low-frequency rolling interactions under resting and inflamed conditions. At the early stage of the response, Treg adhesion was minimal. However, at the peak of inflammation, Tregs made up 40% of the adherent CD4+ T cell population. In a multiple challenge model of contact hypersensitivity, rolling of Tregs and conventional CD4+ T cells was mostly dependent on overlapping contributions of P- and E-selectin. However, after a second challenge, rolling of Tregs but not conventional CD4+ T cells became P-selectin independent, and Tregs showed reduced capacity to bind P-selectin. Moreover, inhibition of E-selectin at this time point resulted in exacerbation of inflammation. These findings demonstrate that in this multiple challenge model of inflammation, Treg selectin binding capacity and the molecular basis of Treg rolling can be regulated dynamically.

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“…More specifically, it is important to understand whether the cell types in the splenocytes that are producing IFNg in response to chitosan are the same as those involved in the footpad swelling response. Several immune cell types including T-cells and macrophages (Doebis et al, 2008) are believed to mediate DTH responses in vivo and were, therefore, expected to be present at the site of the inflammation seen in the footpads of rats sensitized with C. albicans and challenged with chitosan. T-cells were expected to be of particular importance in DTH because sensitivity to C. albicans could be generated in naïve mice by transferring T-cells from immunized animals (Cenci et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a novel delayed-type hypersensitivity assay toCandida albicansin adult and neonatal rats

Thorn¹,

Hudson²,

Kreeger

et al. 2014

Journal of Immunotoxicology

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Delayed-type hypersensitivity (DTH) is a T-cell-mediated immune response that may be used for immunotoxicity testing in non-clinical species. However, in some cases DTH assays using T-dependent antigens may be confounded by the production of antibodies to the antigen. The authors have previously modified a DTH assay, initially validated in the mouse, for use in juvenile rats to assess the effect of immunosuppressive drugs on the developing rat immune system. The assay measures footpad swelling induced by subcutaneous footpad injection of Candida albicans (C. albicans) derived-chitosan in rats previously sensitized with C. albicans. Antibodies to chitosan are not produced in this model. However, considerable inter-animal variability inherent in the footpad swelling assay can make it difficult to precisely quantify the magnitude of the immune response and inhibition by immunosuppressants, particularly if complete suppression is not observed. This report describes the development of an ex vivo assay to assess DTH in rats using interferon (IFN)-g production by splenocytes, obtained from rats sensitized with C. albicans, as the quantifiable measure of the DTH response. Adult and neonatal rats administered dexamethasone (DEX), a known immunosuppressant, exhibited immunosuppression as evidenced by a reduction in ex vivo IFNg production from splenocytes challenged with C. albicans-derived chitosan. Current data indicate that the ex vivo based DTH assay is more sensitive than the conventional footpad swelling assay due to a lower background response and the ability to detect a response as early as post-natal day (PND) 12. The ex vivo based rat DTH assay offers a highly sensitive and quantitative alternative to the footpad swelling assay for the assessment of the immunotoxic potential of drugs. The increased sensitivity of the ex vivo DTH assay may be useful for identifying smaller changes in response to immunotoxic drugs, as well as detecting responses earlier in animal development.

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Cellular Players and Role of Selectin Ligands in Leukocyte Recruitment in a T-Cell-Initiated Delayed-Type Hypersensitivity Reaction

Cited by 19 publications

References 39 publications

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Regulatory T Cells Dynamically Regulate Selectin Ligand Function during Multiple Challenge Contact Hypersensitivity

Evaluation of a novel delayed-type hypersensitivity assay toCandida albicansin adult and neonatal rats

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