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. 1998 Feb 15;101(4):746–754. doi: 10.1172/JCI1422

The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.

S Qin 1, J B Rottman 1, P Myers 1, N Kassam 1, M Weinblatt 1, M Loetscher 1, A E Koch 1, B Moser 1, C R Mackay 1
PMCID: PMC508621  PMID: 9466968

Abstract

T cells infiltrating inflammatory sites are usually of the activated/memory type. The precise mechanism for the positioning of these cells within tissues is unclear. Adhesion molecules certainly play a role; however, the intricate control of cell migration appears to be mediated by numerous chemokines and their receptors. Particularly important chemokines for activated/memory T cells are the CXCR3 ligands IP-10 and Mig and the CCR5 ligands RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta. We raised anti-CXCR3 mAbs and were able to detect high levels of CXCR3 expression on activated T cells. Surprisingly, a proportion of circulating blood T cells, B cells, and natural killer cells also expressed CXCR3. CCR5 showed a similar expression pattern as CXCR3, but was expressed on fewer circulating T cells. Blood T cells expressing CXCR3 (and CCR5) were mostly CD45RO+, and generally expressed high levels of beta1 integrins. This phenotype resembled that of T cells infiltrating inflammatory lesions. Immunostaining of T cells in rheumatoid arthritis synovial fluid confirmed that virtually all such T cells expressed CXCR3 and approximately 80% expressed CCR5, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood, 35 and 15%, respectively. Analysis by immunohistochemistry of various inflamed tissues gave comparable findings in that virtually all T cells within the lesions expressed CXCR3, particularly in perivascular regions, whereas far fewer T cells within normal lymph nodes expressed CXCR3 or CCR5. These results demonstrate that the chemokine receptor CXCR3 and CCR5 are markers for T cells associated with certain inflammatory reactions, particularly TH-1 type reactions. Moreover, CXCR3 and CCR5 appear to identify subsets of T cells in blood with a predilection for homing to these sites.

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Selected References

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  1. Baggiolini M., Dewald B., Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705. doi: 10.1146/annurev.immunol.15.1.675. [DOI] [PubMed] [Google Scholar]
  2. Bleul C. C., Farzan M., Choe H., Parolin C., Clark-Lewis I., Sodroski J., Springer T. A. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996 Aug 29;382(6594):829–833. doi: 10.1038/382829a0. [DOI] [PubMed] [Google Scholar]
  3. Bleul C. C., Fuhlbrigge R. C., Casasnovas J. M., Aiuti A., Springer T. A. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1) J Exp Med. 1996 Sep 1;184(3):1101–1109. doi: 10.1084/jem.184.3.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bleul C. C., Wu L., Hoxie J. A., Springer T. A., Mackay C. R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1925–1930. doi: 10.1073/pnas.94.5.1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Butcher E. C., Picker L. J. Lymphocyte homing and homeostasis. Science. 1996 Apr 5;272(5258):60–66. doi: 10.1126/science.272.5258.60. [DOI] [PubMed] [Google Scholar]
  6. 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. 1996 Jul;134(1):255–266. doi: 10.1083/jcb.134.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carr M. W., Roth S. J., Luther E., Rose S. S., Springer T. A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652–3656. doi: 10.1073/pnas.91.9.3652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chuntharapai A., Lee J., Burnier J., Wood W. I., Hébert C., Kim K. J. Neutralizing monoclonal antibodies to human IL-8 receptor A map to the NH2-terminal region of the receptor. J Immunol. 1994 Feb 15;152(4):1783–1789. [PubMed] [Google Scholar]
  9. Chuntharapai A., Lee J., Hébert C. A., Kim K. J. Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes. J Immunol. 1994 Dec 15;153(12):5682–5688. [PubMed] [Google Scholar]
  10. Heath H., Qin S., Rao P., Wu L., LaRosa G., Kassam N., Ponath P. D., Mackay C. R. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J Clin Invest. 1997 Jan 15;99(2):178–184. doi: 10.1172/JCI119145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kaplan G., Luster A. D., Hancock G., Cohn Z. A. The expression of a gamma interferon-induced protein (IP-10) in delayed immune responses in human skin. J Exp Med. 1987 Oct 1;166(4):1098–1108. doi: 10.1084/jem.166.4.1098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kondo T., Novick A. C., Toma H., Fairchild R. L. Induction of chemokine gene expression during allogeneic skin graft rejection. Transplantation. 1996 Jun 27;61(12):1750–1757. doi: 10.1097/00007890-199606270-00015. [DOI] [PubMed] [Google Scholar]
  13. Liao F., Rabin R. L., Yannelli J. R., Koniaris L. G., Vanguri P., Farber J. M. Human Mig chemokine: biochemical and functional characterization. J Exp Med. 1995 Nov 1;182(5):1301–1314. doi: 10.1084/jem.182.5.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Loetscher M., Gerber B., Loetscher P., Jones S. A., Piali L., Clark-Lewis I., Baggiolini M., Moser B. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med. 1996 Sep 1;184(3):963–969. doi: 10.1084/jem.184.3.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mackay C. R. Chemokines: what chemokine is that? Curr Biol. 1997 Jun 1;7(6):R384–R386. doi: 10.1016/s0960-9822(06)00181-3. [DOI] [PubMed] [Google Scholar]
  16. Mackay C. R. Homing of naive, memory and effector lymphocytes. Curr Opin Immunol. 1993 Jun;5(3):423–427. doi: 10.1016/0952-7915(93)90063-x. [DOI] [PubMed] [Google Scholar]
  17. Monteclaro F. S., Charo I. F. The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1alpha receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation. J Biol Chem. 1996 Aug 9;271(32):19084–19092. doi: 10.1074/jbc.271.32.19084. [DOI] [PubMed] [Google Scholar]
  18. Oberlin E., Amara A., Bachelerie F., Bessia C., Virelizier J. L., Arenzana-Seisdedos F., Schwartz O., Heard J. M., Clark-Lewis I., Legler D. F. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833–835. doi: 10.1038/382833a0. [DOI] [PubMed] [Google Scholar]
  19. Oppenheimer-Marks N., Lipsky P. E. Migration of naive and memory T cells. Immunol Today. 1997 Sep;18(9):456–457. doi: 10.1016/s0167-5699(97)82723-5. [DOI] [PubMed] [Google Scholar]
  20. Pitzalis C., Kingsley G., Haskard D., Panayi G. The preferential accumulation of helper-inducer T lymphocytes in inflammatory lesions: evidence for regulation by selective endothelial and homotypic adhesion. Eur J Immunol. 1988 Sep;18(9):1397–1404. doi: 10.1002/eji.1830180915. [DOI] [PubMed] [Google Scholar]
  21. Ponath P. D., Qin S., Ringler D. J., Clark-Lewis I., Wang J., Kassam N., Smith H., Shi X., Gonzalo J. A., Newman W. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest. 1996 Feb 1;97(3):604–612. doi: 10.1172/JCI118456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Qin S., LaRosa G., Campbell J. J., Smith-Heath H., Kassam N., Shi X., Zeng L., Buthcher E. C., Mackay C. R. Expression of monocyte chemoattractant protein-1 and interleukin-8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential. Eur J Immunol. 1996 Mar;26(3):640–647. doi: 10.1002/eji.1830260320. [DOI] [PubMed] [Google Scholar]
  23. Ransohoff R. M., Hamilton T. A., Tani M., Stoler M. H., Shick H. E., Major J. A., Estes M. L., Thomas D. M., Tuohy V. K. Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J. 1993 Apr 1;7(6):592–600. doi: 10.1096/fasebj.7.6.8472896. [DOI] [PubMed] [Google Scholar]
  24. Sallusto F., Mackay C. R., Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science. 1997 Sep 26;277(5334):2005–2007. doi: 10.1126/science.277.5334.2005. [DOI] [PubMed] [Google Scholar]
  25. Salmi M., Andrew D. P., Butcher E. C., Jalkanen S. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J Exp Med. 1995 Jan 1;181(1):137–149. doi: 10.1084/jem.181.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schall T. J., Bacon K., Toy K. J., Goeddel D. V. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature. 1990 Oct 18;347(6294):669–671. doi: 10.1038/347669a0. [DOI] [PubMed] [Google Scholar]
  27. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  28. Strieter R. M., Standiford T. J., Huffnagle G. B., Colletti L. M., Lukacs N. W., Kunkel S. L. "The good, the bad, and the ugly." The role of chemokines in models of human disease. J Immunol. 1996 May 15;156(10):3583–3586. [PubMed] [Google Scholar]
  29. Taub D. D., Conlon K., Lloyd A. R., Oppenheim J. J., Kelvin D. J. Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science. 1993 Apr 16;260(5106):355–358. doi: 10.1126/science.7682337. [DOI] [PubMed] [Google Scholar]
  30. Taub D. D., Lloyd A. R., Conlon K., Wang J. M., Ortaldo J. R., Harada A., Matsushima K., Kelvin D. J., Oppenheim J. J. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med. 1993 Jun 1;177(6):1809–1814. doi: 10.1084/jem.177.6.1809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Taub D. D., Proost P., Murphy W. J., Anver M., Longo D. L., van Damme J., Oppenheim J. J. Monocyte chemotactic protein-1 (MCP-1), -2, and -3 are chemotactic for human T lymphocytes. J Clin Invest. 1995 Mar;95(3):1370–1376. doi: 10.1172/JCI117788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Uguccioni M., Mackay C. R., Ochensberger B., Loetscher P., Rhis S., LaRosa G. J., Rao P., Ponath P. D., Baggiolini M., Dahinden C. A. High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines. J Clin Invest. 1997 Sep 1;100(5):1137–1143. doi: 10.1172/JCI119624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wu L., Gerard N. P., Wyatt R., Choe H., Parolin C., Ruffing N., Borsetti A., Cardoso A. A., Desjardin E., Newman W. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996 Nov 14;384(6605):179–183. doi: 10.1038/384179a0. [DOI] [PubMed] [Google Scholar]
  34. Wu L., LaRosa G., Kassam N., Gordon C. J., Heath H., Ruffing N., Chen H., Humblias J., Samson M., Parmentier M. Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. J Exp Med. 1997 Oct 20;186(8):1373–1381. doi: 10.1084/jem.186.8.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wu L., Paxton W. A., Kassam N., Ruffing N., Rottman J. B., Sullivan N., Choe H., Sodroski J., Newman W., Koup R. A. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J Exp Med. 1997 May 5;185(9):1681–1691. doi: 10.1084/jem.185.9.1681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wu L., Ruffing N., Shi X., Newman W., Soler D., Mackay C. R., Qin S. Discrete steps in binding and signaling of interleukin-8 with its receptor. J Biol Chem. 1996 Dec 6;271(49):31202–31209. doi: 10.1074/jbc.271.49.31202. [DOI] [PubMed] [Google Scholar]

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