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The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells

Abstract

Lymphocytes that are responsible for regional (tissue-specific) immunity home from the blood to the intestines, inflamed skin or other sites through a multistep process involving recognition of vascular endothelial cells and extravasation1. Chemoattractant cytokine molecules known as chemokines2 regulate this lymphocyte traffic, in part by triggering arrest (stopping) of lymphocytes rolling on endothelium3,4,5. Here we show that many systemic memory T cells in blood carry the chemokine receptor CCR4 (ref. 6) and therefore respond to its ligands, the chemokines TARC and MDC. These cells include essentially all skin-homing cells expressing the cutaneous lymphocyte antigen and a subset of other systemic memory lymphocytes; however, intestinal (α4β7+) memory and naive T cells respond poorly. Immunohistochemistry reveals anti-TARC reactivity of venules and infiltration of many CCR4+ lymphocytes in chronically inflamed skin, but not in the gastrointestinal lamina propria. Moreover, TARC induces integrin-dependent adhesion of skin (but not intestinal) memory T cells to the cell-adhesion molecule ICAM-1, and causes their rapid arrest under physiological flow. Our results suggest that CCR4 and TARC are important in the recognition of skin vasculature by circulating T cells and in directing lymphocytes that are involved in systemic as opposed to intestinal immunity to their target tissues.

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Figure 1: A major subset of systemic memory CD4 T cells (including skin-homing cells) is preferentially attracted by TARC and MDC, and expresses CCR.
Figure 2: Anti-TARC reactive venules and infiltrating CCR4+ cells in inflammatory skin lesions.
Figure 3: TARC and rapid ICAM-1 adhesion.

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Acknowledgements

We thank L. Rott for important advice on flow cytometry and cell separation, E.Resurreccion for immunohistology, and E. Pfendt for frozen tissue archiving. Some tissues were obtained from the National Disease Research Interchange, a service organization funded by the NIH, or from the Human Cooperative Tissue Network. This work was supported by grants from the NIH and an Award from the Department of Veterans Affairs (E.C.B.) and by the FACS Core Facility of the Stanford Digestive Disease Center. G.H. was supported by the Norwegian Cancer Society, J.J.C. was supported by a grant from the NIH Cancer Etiology, Prevention, Detection, and Diagnosis, and by an NIH Individual National Research Service award. J.J.C. and J.P. are recipiants of postdoctoral fellowships from the Arthritis Foundation.

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Correspondence to J. J. Campbell, D. P. Andrew or L. Wu.

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Campbell, J., Haraldsen, G., Pan, J. et al. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776–780 (1999). https://doi.org/10.1038/23495

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