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. 1991 Jun 1;113(5):1203–1212. doi: 10.1083/jcb.113.5.1203

Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions

PMCID: PMC2289015  PMID: 1710227

Abstract

T cell adhesion to endothelium is critical to lymphocyte recirculation and influx into sites of inflammation. We have systematically analyzed the role of four receptor/ligand interactions that mediate adhesion of peripheral human CD4+ T cells to cultured human umbilical vein endothelial cells (HUVEC): T cell LFA-1 binding to ICAM-1 and an alternative ligand ("ICAM-X"), T cell VLA-4 binding to VCAM-1, and T cell binding to ELAM-1. Contributions of these four pathways depend on the activation state of both the T cell and HUVEC, and the differentiation state of the T cell. ELAM-1 plays a significant role in mediating adhesion of resting CD4+ T cells to activated HUVEC. LFA-1 adhesion dominates with PMA-activated T cells but the strength and predominant LFA-1 ligand is determined by the activation state of the HUVEC; while ICAM-1 is the dominant ligand on IL-1-induced HUVEC, "ICAM- X" dominates binding to uninduced HUVEC. Adhesion via VLA-4 depends on induction of its ligand VCAM-1 on activated HUVEC; PMA activation of T cells augments VLA-4-mediated adhesion, both in the model of T/HUVEC binding and in a simplified model of T cell adhesion to VCAM-1- transfected L cells. Unlike LFA-1 and VLA-4, ELAM-1-mediated adhesion is not increased by T cell activation. Differential expression of adhesion molecules on CD4+ T cell subsets understood to be naive and memory cells also regulates T/HUVEC adhesion. Naive T cell adhesion to HUVEC is mediated predominantly by LFA-1 with little or no involvement of the VLA-4 and ELAM-1 pathways. In contrast, memory T cells bind better to HUVEC and utilize all four pathways. These studies demonstrate that there are at least four molecular pathways mediating T/HUVEC adhesion and that the dominance/hierarchy of these pathways varies dramatically with the activation state of the interacting cells and the differentiation state of the T cell.

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Selected References

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  1. Arnaout M. A. Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response. Immunol Rev. 1990 Apr;114:145–180. doi: 10.1111/j.1600-065x.1990.tb00564.x. [DOI] [PubMed] [Google Scholar]
  2. Bevilacqua M. P., Pober J. S., Mendrick D. L., Cotran R. S., Gimbrone M. A., Jr Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9238–9242. doi: 10.1073/pnas.84.24.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bevilacqua M. P., Stengelin S., Gimbrone M. A., Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989 Mar 3;243(4895):1160–1165. doi: 10.1126/science.2466335. [DOI] [PubMed] [Google Scholar]
  4. Boyd A. W., Wawryk S. O., Burns G. F., Fecondo J. V. Intercellular adhesion molecule 1 (ICAM-1) has a central role in cell-cell contact-mediated immune mechanisms. Proc Natl Acad Sci U S A. 1988 May;85(9):3095–3099. doi: 10.1073/pnas.85.9.3095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Camerini D., James S. P., Stamenkovic I., Seed B. Leu-8/TQ1 is the human equivalent of the Mel-14 lymph node homing receptor. Nature. 1989 Nov 2;342(6245):78–82. doi: 10.1038/342078a0. [DOI] [PubMed] [Google Scholar]
  6. Carlos T. M., Schwartz B. R., Kovach N. L., Yee E., Rosa M., Osborn L., Chi-Rosso G., Newman B., Lobb R., Rosso M. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood. 1990 Sep 1;76(5):965–970. [PubMed] [Google Scholar]
  7. Cavender D. E., Haskard D. O., Maliakkal D., Ziff M. Separation and characterization of human T lymphocytes with varying adhesiveness for endothelial cells. Cell Immunol. 1988 Nov;117(1):111–126. doi: 10.1016/0008-8749(88)90081-0. [DOI] [PubMed] [Google Scholar]
  8. Clayberger C., Krensky A. M., McIntyre B. W., Koller T. D., Parham P., Brodsky F., Linn D. J., Evans E. L. Identification and characterization of two novel lymphocyte function-associated antigens, L24 and L25. J Immunol. 1987 Mar 1;138(5):1510–1514. [PubMed] [Google Scholar]
  9. Damle N. K., Doyle L. V. Ability of human T lymphocytes to adhere to vascular endothelial cells and to augment endothelial permeability to macromolecules is linked to their state of post-thymic maturation. J Immunol. 1990 Feb 15;144(4):1233–1240. [PubMed] [Google Scholar]
  10. Dustin M. L., Springer T. A. Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol. 1988 Jul;107(1):321–331. doi: 10.1083/jcb.107.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dustin M. L., Springer T. A. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature. 1989 Oct 19;341(6243):619–624. doi: 10.1038/341619a0. [DOI] [PubMed] [Google Scholar]
  12. Elices M. J., Osborn L., Takada Y., Crouse C., Luhowskyj S., Hemler M. E., Lobb R. R. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990 Feb 23;60(4):577–584. doi: 10.1016/0092-8674(90)90661-w. [DOI] [PubMed] [Google Scholar]
  13. Garcia-Pardo A., Wayner E. A., Carter W. G., Ferreira O. C., Jr Human B lymphocytes define an alternative mechanism of adhesion to fibronectin. The interaction of the alpha 4 beta 1 integrin with the LHGPEILDVPST sequence of the type III connecting segment is sufficient to promote cell attachment. J Immunol. 1990 May 1;144(9):3361–3366. [PubMed] [Google Scholar]
  14. Geoffroy J. S., Rosen S. D. Demonstration that a lectin-like receptor (gp90MEL) directly mediates adhesion of lymphocytes to high endothelial venules of lymph nodes. J Cell Biol. 1989 Nov;109(5):2463–2469. doi: 10.1083/jcb.109.5.2463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Graber N., Gopal T. V., Wilson D., Beall L. D., Polte T., Newman W. T cells bind to cytokine-activated endothelial cells via a novel, inducible sialoglycoprotein and endothelial leukocyte adhesion molecule-1. J Immunol. 1990 Aug 1;145(3):819–830. [PubMed] [Google Scholar]
  16. Guan J. L., Hynes R. O. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell. 1990 Jan 12;60(1):53–61. doi: 10.1016/0092-8674(90)90715-q. [DOI] [PubMed] [Google Scholar]
  17. Hildreth J. E., Gotch F. M., Hildreth P. D., McMichael A. J. A human lymphocyte-associated antigen involved in cell-mediated lympholysis. Eur J Immunol. 1983 Mar;13(3):202–208. doi: 10.1002/eji.1830130305. [DOI] [PubMed] [Google Scholar]
  18. Horgan K. J., Van Seventer G. A., Shimizu Y., Shaw S. Hyporesponsiveness of "naive" (CD45RA+) human T cells to multiple receptor-mediated stimuli but augmentation of responses by co-stimuli. Eur J Immunol. 1990 May;20(5):1111–1118. doi: 10.1002/eji.1830200525. [DOI] [PubMed] [Google Scholar]
  19. Issekutz T. B., Issekutz A. C., Movat H. Z. The in vivo quantitation and kinetics of monocyte migration into acute inflammatory tissue. Am J Pathol. 1981 Apr;103(1):47–55. [PMC free article] [PubMed] [Google Scholar]
  20. James S. P., Fiocchi C., Graeff A. S., Strober W. Phenotypic analysis of lamina propria lymphocytes. Predominance of helper-inducer and cytolytic T-cell phenotypes and deficiency of suppressor-inducer phenotypes in Crohn's disease and control patients. Gastroenterology. 1986 Dec;91(6):1483–1489. [PubMed] [Google Scholar]
  21. Janossy G., Bofill M., Rowe D., Muir J., Beverley P. C. The tissue distribution of T lymphocytes expressing different CD45 polypeptides. Immunology. 1989 Apr;66(4):517–525. [PMC free article] [PubMed] [Google Scholar]
  22. Kingsley G., Pitzalis C., Kyriazis N., Panayi G. S. Abnormal helper-inducer/suppressor-inducer T-cell subset distribution and T-cell activation status are common to all types of chronic synovitis. Scand J Immunol. 1988 Aug;28(2):225–232. doi: 10.1111/j.1365-3083.1988.tb02435.x. [DOI] [PubMed] [Google Scholar]
  23. Ledbetter J. A., Clark E. A. Surface phenotype and function of tonsillar germinal center and mantle zone B cell subsets. Hum Immunol. 1986 Jan;15(1):30–43. doi: 10.1016/0198-8859(86)90315-0. [DOI] [PubMed] [Google Scholar]
  24. Mackay C. R., Marston W. L., Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med. 1990 Mar 1;171(3):801–817. doi: 10.1084/jem.171.3.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Makgoba M. W., Sanders M. E., Ginther Luce G. E., Dustin M. L., Springer T. A., Clark E. A., Mannoni P., Shaw S. ICAM-1 a ligand for LFA-1-dependent adhesion of B, T and myeloid cells. Nature. 1988 Jan 7;331(6151):86–88. doi: 10.1038/331086a0. [DOI] [PubMed] [Google Scholar]
  26. Makgoba M. W., Sanders M. E., Shaw S. The CD2-LFA-3 and LFA-1-ICAM pathways: relevance to T-cell recognition. Immunol Today. 1989 Dec;10(12):417–422. doi: 10.1016/0167-5699(89)90039-X. [DOI] [PubMed] [Google Scholar]
  27. Marlin S. D., Springer T. A. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell. 1987 Dec 4;51(5):813–819. doi: 10.1016/0092-8674(87)90104-8. [DOI] [PubMed] [Google Scholar]
  28. Masinovsky B., Urdal D., Gallatin W. M. IL-4 acts synergistically with IL-1 beta to promote lymphocyte adhesion to microvascular endothelium by induction of vascular cell adhesion molecule-1. J Immunol. 1990 Nov 1;145(9):2886–2895. [PubMed] [Google Scholar]
  29. Matsuyama T., Yamada A., Kay J., Yamada K. M., Akiyama S. K., Schlossman S. F., Morimoto C. Activation of CD4 cells by fibronectin and anti-CD3 antibody. A synergistic effect mediated by the VLA-5 fibronectin receptor complex. J Exp Med. 1989 Oct 1;170(4):1133–1148. doi: 10.1084/jem.170.4.1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Oppenheimer-Marks N., Davis L. S., Lipsky P. E. Human T lymphocyte adhesion to endothelial cells and transendothelial migration. Alteration of receptor use relates to the activation status of both the T cell and the endothelial cell. J Immunol. 1990 Jul 1;145(1):140–148. [PubMed] [Google Scholar]
  31. Osborn L., Hession C., Tizard R., Vassallo C., Luhowskyj S., Chi-Rosso G., Lobb R. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell. 1989 Dec 22;59(6):1203–1211. doi: 10.1016/0092-8674(89)90775-7. [DOI] [PubMed] [Google Scholar]
  32. Osborn L. Leukocyte adhesion to endothelium in inflammation. Cell. 1990 Jul 13;62(1):3–6. doi: 10.1016/0092-8674(90)90230-c. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Pober J. S., Bevilacqua M. P., Mendrick D. L., Lapierre L. A., Fiers W., Gimbrone M. A., Jr Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol. 1986 Mar 1;136(5):1680–1687. [PubMed] [Google Scholar]
  35. Rice G. E., Munro J. M., Bevilacqua M. P. Inducible cell adhesion molecule 110 (INCAM-110) is an endothelial receptor for lymphocytes. A CD11/CD18-independent adhesion mechanism. J Exp Med. 1990 Apr 1;171(4):1369–1374. doi: 10.1084/jem.171.4.1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sanders M. E., Makgoba M. W., Sharrow S. O., Stephany D., Springer T. A., Young H. A., Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production. J Immunol. 1988 Mar 1;140(5):1401–1407. [PubMed] [Google Scholar]
  37. Sanders M. E., Makgoba M. W., Shaw S. Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today. 1988 Jul-Aug;9(7-8):195–199. doi: 10.1016/0167-5699(88)91212-1. [DOI] [PubMed] [Google Scholar]
  38. Schwartz B. R., Wayner E. A., Carlos T. M., Ochs H. D., Harlan J. M. Identification of surface proteins mediating adherence of CD11/CD18-deficient lymphoblastoid cells to cultured human endothelium. J Clin Invest. 1990 Jun;85(6):2019–2022. doi: 10.1172/JCI114668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Shaw S., Luce G. E., Quinones R., Gress R. E., Springer T. A., Sanders M. E. Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones. Nature. 1986 Sep 18;323(6085):262–264. doi: 10.1038/323262a0. [DOI] [PubMed] [Google Scholar]
  40. Shaw S., Shimizu Y. Two molecular pathways of human T cell adhesion: establishment of receptor-ligand relationship. Curr Opin Immunol. 1988 Sep-Oct;1(1):92–97. doi: 10.1016/0952-7915(88)90058-1. [DOI] [PubMed] [Google Scholar]
  41. Shimizu Y., Shaw S., Graber N., Gopal T. V., Horgan K. J., Van Seventer G. A., Newman W. Activation-independent binding of human memory T cells to adhesion molecule ELAM-1. Nature. 1991 Feb 28;349(6312):799–802. doi: 10.1038/349799a0. [DOI] [PubMed] [Google Scholar]
  42. Shimizu Y., Van Seventer G. A., Horgan K. J., Shaw S. Regulated expression and binding of three VLA (beta 1) integrin receptors on T cells. Nature. 1990 May 17;345(6272):250–253. doi: 10.1038/345250a0. [DOI] [PubMed] [Google Scholar]
  43. Shimizu Y., van Seventer G. A., Horgan K. J., Shaw S. Costimulation of proliferative responses of resting CD4+ T cells by the interaction of VLA-4 and VLA-5 with fibronectin or VLA-6 with laminin. J Immunol. 1990 Jul 1;145(1):59–67. [PubMed] [Google Scholar]
  44. Shimizu Y., van Seventer G. A., Horgan K. J., Shaw S. Roles of adhesion molecules in T-cell recognition: fundamental similarities between four integrins on resting human T cells (LFA-1, VLA-4, VLA-5, VLA-6) in expression, binding, and costimulation. Immunol Rev. 1990 Apr;114:109–143. doi: 10.1111/j.1600-065x.1990.tb00563.x. [DOI] [PubMed] [Google Scholar]
  45. Siegelman M. H., van de Rijn M., Weissman I. L. Mouse lymph node homing receptor cDNA clone encodes a glycoprotein revealing tandem interaction domains. Science. 1989 Mar 3;243(4895):1165–1172. doi: 10.1126/science.2646713. [DOI] [PubMed] [Google Scholar]
  46. Smith S. H., Brown M. H., Rowe D., Callard R. E., Beverley P. C. Functional subsets of human helper-inducer cells defined by a new monoclonal antibody, UCHL1. Immunology. 1986 May;58(1):63–70. [PMC free article] [PubMed] [Google Scholar]
  47. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  48. Staunton D. E., Dustin M. L., Springer T. A. Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1. Nature. 1989 May 4;339(6219):61–64. doi: 10.1038/339061a0. [DOI] [PubMed] [Google Scholar]
  49. Stoolman L. M. Adhesion molecules controlling lymphocyte migration. Cell. 1989 Mar 24;56(6):907–910. doi: 10.1016/0092-8674(89)90620-x. [DOI] [PubMed] [Google Scholar]
  50. Takada Y., Elices M. J., Crouse C., Hemler M. E. The primary structure of the alpha 4 subunit of VLA-4: homology to other integrins and a possible cell-cell adhesion function. EMBO J. 1989 May;8(5):1361–1368. doi: 10.1002/j.1460-2075.1989.tb03516.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Taylor R. G., Lewis J. C. Endothelial cell proliferation and monocyte adhesion to atherosclerotic lesions of white carneau pigeons. Am J Pathol. 1986 Oct;125(1):152–160. [PMC free article] [PubMed] [Google Scholar]
  52. Van Seventer G. A., Shimizu Y., Horgan K. J., Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990 Jun 15;144(12):4579–4586. [PubMed] [Google Scholar]
  53. Wayner E. A., Garcia-Pardo A., Humphries M. J., McDonald J. A., Carter W. G. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol. 1989 Sep;109(3):1321–1330. doi: 10.1083/jcb.109.3.1321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yednock T. A., Rosen S. D. Lymphocyte homing. Adv Immunol. 1989;44:313–378. doi: 10.1016/s0065-2776(08)60645-8. [DOI] [PubMed] [Google Scholar]
  55. van Kooyk Y., van de Wiel-van Kemenade P., Weder P., Kuijpers T. W., Figdor C. G. Enhancement of LFA-1-mediated cell adhesion by triggering through CD2 or CD3 on T lymphocytes. Nature. 1989 Dec 14;342(6251):811–813. doi: 10.1038/342811a0. [DOI] [PubMed] [Google Scholar]

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