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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Butcher, E. C., Williams, M., Youngman, K., Rott, L. & Briskin, M. Lymphocyte trafficking and regional immunity. Adv. Immunol. 72, 209–253 (1999).
Zlotnik, A., Morales, J. & Hedrick, JA. Recent advances in chemokines and chemokine receptor. Crit. Rev. Immunol. 19, 1–47 (1999).
Butcher, E. C. Leukocyte–endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67, 1033–1036 (1991).
Campbell, JJ. et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381–384 (1998).
Gunn, M. D. et al. Achemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl Acad. Sci. USA 95, 258–263 (1998).
Power, C. A. et al. Molecular cloning and functional expression of a novel CC chemokine receptor cDNA from a human basophilic cell line. J. Biol. Chem. 270, 19495–19500 (1995).
Campbell, J. J., Qin, S., Bacon, K. B., Mackay, C. R. & Butcher, E. C. Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. J. Cell Biol. 134, 255–266 (1996).
Campbell, J. J. et al. 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3β receptor CCR7. J. Cell Biol. 141, 1053–1059 (1998).
Mackay, C. R., Andrew,,, D. P., Briskin, M., Ringler, D. J. & Butcher, E. C. Phenotype and migration properties of three major subsets of tissue homing T cells in sheep. Eur. J. Immunol. 26, 2433–2439 (1996).
Williams, M. B. & butcher, E. C. Homing of naive and memory T lymphocyte subsets to Peyer's patches, lymph nodes, and spleen. J. Immunol. 159, 1746–1752 (1997).
Santamaria Babi, L. F. et al. Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen. J. Exp. Med. 181, 1935–1940 (1995).
Picker, L. J., Michie, S. A., Rott, L. S. & Butcher, E. C. Aunique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am. J. Pathol. 136, 1053–1068 (1990).
Berg, E. L. et al. The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1. J. Exp. Med. 174, 1461–1466 (1991).
Anderson, A. O. & Shaw, S. T-cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node. Semin. Immunol. 5, 271–282 (1993).
Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).
Utgaard, J. O., Jahnsen, F. L., Bakka, A., Brandtzaeg, P. & Haraldsen, G. Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells. J. Exp. Med. 188, 1751–1756 (1998).
Baekkevold, E. S. et al. Culture characterization of differentiated high endothelial venule cells from human tonsils. Lab. Invest. 79, 327–336 (1999).
Silber, A. et al. Recruitment of lymphocytes during cutaneous delayed hypersensitivity in nonhuman primates is dependent on E-selectin and vascular cell adhesion molecule 1. J. Clin. Invest. 93, 1554–1563 (1994).
Balashov, K. E., Rottman, J. B., Weiner, H. L. & Hancock, W. W. CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1α and IP-10 are expressed in demyelinating brain lesions. Proc. Natl Acad. Sci. USA 96, 6873–6878 (1999).
Picker, L. J., Kishimoto, T. K., Smith, C. W., Warnock, R. A. & Butcher, E. C. ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 349, 796–799 (1991).
Imai, T., Baba, M., Nishimua, M., Takagi, S. & Yoshie, O. The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J. Biol. Chem. 272, 15036–15042 (1997).
Bonecchi, R. et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 187, 129–134 (1998).
Andrew, D. P. et al. STCP-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13. J. Immunol. 161, 5027–5038 (1998).
Sallusto, F., Lenig, D., Mackay, C. R. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875–883 (1998).
Austrup, F. et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 385, 81–83 (1997).
Sallusto, F., Lanzavecchia, A. & Mackay, C. R. Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol. Today 19, 568–574 (1998).
D'Ambrosio, D. et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J. Immunol. 161, 5111–5115 (1998).
Teraki, Y. & Picker, L. J. Independent regulation of cutaneous lymphocyte-associated antigen expression and cytokine synthesis phenotype during human CD4+ memory T cell differentiation. J. Immunol. 159, 6018–6029 (1997).
Qin, S. et al. the chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101, 746–754 (1998).
Qin, S. et al. Expression of monocyte chemoattractant protein-1 and interleukin-8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential. Eur. J. Immunol. 26, 640–647 (1996).
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.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/23495
This article is cited by
-
Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice
Journal of NeuroVirology (2024)
-
A review of the pleiotropic actions of the IFN-inducible CXC chemokine receptor 3 ligands in the synovial microenvironment
Cellular and Molecular Life Sciences (2023)
-
Bitter taste receptor T2R38 is expressed on skin-infiltrating lymphocytes and regulates lymphocyte migration
Scientific Reports (2022)
-
Safety and efficacy profile of mogamulizumab (Poteligeo) in the treatment of cancers: an update evidence from 14 studies
BMC Cancer (2021)
-
SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8+ T cells
Nature Communications (2020)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.