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. 1991 Aug;88(2):546–552. doi: 10.1172/JCI115338

Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis.

A Laffón 1, R García-Vicuña 1, A Humbría 1, A A Postigo 1, A L Corbí 1, M O de Landázuri 1, F Sánchez-Madrid 1
PMCID: PMC295383  PMID: 1830891

Abstract

The VLA-4 (CD49d/CD29) integrin is a cell surface receptor involved in the interaction of lymphoid cells with both extracellular matrix (ECM) and endothelial cells. We have investigated the expression and function of VLA-4 fibronectin (FN) receptors on T cells localized in the inflammed synovium of patients with rheumatoid arthritis (RA). A high proportion of T cells in both synovial membrane (SM) and synovial fluid (SF) expressed the activation antigens AIM (CD69) and gp95/85 (Ea2) as well as an increased number of VLA-4 alpha and beta 1 adhesion molecules, as compared with peripheral blood (PB) T cells from the same patients. Furthermore, the majority of these activated SF T cells were able to adhere to a 38-kD FN proteolytic fragment containing the connecting segment-1 (CS-1) specifically through VLA-4 receptors, whereas a significantly lower proportion of PB T cells displayed this capacity. Therefore, our results show that activated T cells selectively localize at sites of tissue injury in RA disease and provide evidence for the in vivo regulation of the expression and function of the VLA-4 integrin. This regulatory mechanism may enable T cells either to facilitate migration or to persist at sites of inflammation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akbar A. N., Terry L., Timms A., Beverley P. C., Janossy G. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol. 1988 Apr 1;140(7):2171–2178. [PubMed] [Google Scholar]
  2. Altieri D. C., Edgington T. S. The saturable high affinity association of factor X to ADP-stimulated monocytes defines a novel function of the Mac-1 receptor. J Biol Chem. 1988 May 25;263(15):7007–7015. [PubMed] [Google Scholar]
  3. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  4. Bednarczyk J. L., McIntyre B. W. A monoclonal antibody to VLA-4 alpha-chain (CDw49d) induces homotypic lymphocyte aggregation. J Immunol. 1990 Feb 1;144(3):777–784. [PubMed] [Google Scholar]
  5. Burmester G. R., Yu D. T., Irani A. M., Kunkel H. G., Winchester R. J. Ia+ T cells in synovial fluid and tissues of patients with rheumatoid arthritis. Arthritis Rheum. 1981 Nov;24(11):1370–1376. doi: 10.1002/art.1780241106. [DOI] [PubMed] [Google Scholar]
  6. Campanero M. R., Pulido R., Ursa M. A., Rodríguez-Moya M., de Landázuri M. O., Sánchez-Madrid F. An alternative leukocyte homotypic adhesion mechanism, LFA-1/ICAM-1-independent, triggered through the human VLA-4 integrin. J Cell Biol. 1990 Jun;110(6):2157–2165. doi: 10.1083/jcb.110.6.2157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carsons S., Mosesson M. W., Diamond H. S. Detection and quantitation of fibronectin in synovial fluid from patients with rheumatic disease. Arthritis Rheum. 1981 Oct;24(10):1261–1267. [PubMed] [Google Scholar]
  8. Cavender D., Haskard D., Yu C. L., Iguchi T., Miossec P., Oppenheimer-Marks N., Ziff M. Pathways to chronic inflammation in rheumatoid synovitis. Fed Proc. 1987 Jan;46(1):113–117. [PubMed] [Google Scholar]
  9. Cebrián M., Yagüe E., Rincón M., López-Botet M., de Landázuri M. O., Sánchez-Madrid F. Triggering of T cell proliferation through AIM, an activation inducer molecule expressed on activated human lymphocytes. J Exp Med. 1988 Nov 1;168(5):1621–1637. doi: 10.1084/jem.168.5.1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chatila T. A., Geha R. S., Arnaout M. A. Constitutive and stimulus-induced phosphorylation of CD11/CD18 leukocyte adhesion molecules. J Cell Biol. 1989 Dec;109(6 Pt 2):3435–3444. doi: 10.1083/jcb.109.6.3435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Clemmensen I., Andersen R. B. Different molecular forms of fibronectin in rheumatoid synovial fluid. Arthritis Rheum. 1982 Jan;25(1):25–31. doi: 10.1002/art.1780250104. [DOI] [PubMed] [Google Scholar]
  13. Cush J. J., Lipsky P. E. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Oct;31(10):1230–1238. doi: 10.1002/art.1780311003. [DOI] [PubMed] [Google Scholar]
  14. De Strooper B., Van der Schueren B., Jaspers M., Saison M., Spaepen M., Van Leuven F., Van den Berghe H., Cassiman J. J. Distribution of the beta 1 subgroup of the integrins in human cells and tissues. J Histochem Cytochem. 1989 Mar;37(3):299–307. doi: 10.1177/37.3.2645360. [DOI] [PubMed] [Google Scholar]
  15. Detmers P. A., Wright S. D., Olsen E., Kimball B., Cohn Z. A. Aggregation of complement receptors on human neutrophils in the absence of ligand. J Cell Biol. 1987 Sep;105(3):1137–1145. doi: 10.1083/jcb.105.3.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. 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]
  19. Ginsberg M. H., Loftus J. C., Plow E. F. Cytoadhesins, integrins, and platelets. Thromb Haemost. 1988 Feb 25;59(1):1–6. [PubMed] [Google Scholar]
  20. Hemler M. E. Adhesive protein receptors on hematopoietic cells. Immunol Today. 1988 Apr;9(4):109–113. doi: 10.1016/0167-5699(88)91280-7. [DOI] [PubMed] [Google Scholar]
  21. Hemler M. E., Elices M. J., Parker C., Takada Y. Structure of the integrin VLA-4 and its cell-cell and cell-matrix adhesion functions. Immunol Rev. 1990 Apr;114:45–65. doi: 10.1111/j.1600-065x.1990.tb00561.x. [DOI] [PubMed] [Google Scholar]
  22. Hemler M. E., Glass D., Coblyn J. S., Jacobson J. G. Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation. J Clin Invest. 1986 Sep;78(3):696–702. doi: 10.1172/JCI112629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hemler M. E., Sanchez-Madrid F., Flotte T. J., Krensky A. M., Burakoff S. J., Bhan A. K., Springer T. A., Strominger J. L. Glycoproteins of 210,000 and 130,000 m.w. on activated T cells: cell distribution and antigenic relation to components on resting cells and T cell lines. J Immunol. 1984 Jun;132(6):3011–3018. [PubMed] [Google Scholar]
  24. Hemler M. E. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365–400. doi: 10.1146/annurev.iy.08.040190.002053. [DOI] [PubMed] [Google Scholar]
  25. Herbert K. E., Coppock J. S., Griffiths A. M., Williams A., Robinson M. W., Scott D. L. Fibronectin and immune complexes in rheumatic diseases. Ann Rheum Dis. 1987 Oct;46(10):734–740. doi: 10.1136/ard.46.10.734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Holzmann B., Weissman I. L. Integrin molecules involved in lymphocyte homing to Peyer's patches. Immunol Rev. 1989 Apr;108:45–61. doi: 10.1111/j.1600-065x.1989.tb00012.x. [DOI] [PubMed] [Google Scholar]
  27. Hynes R. O. Integrins: a family of cell surface receptors. Cell. 1987 Feb 27;48(4):549–554. doi: 10.1016/0092-8674(87)90233-9. [DOI] [PubMed] [Google Scholar]
  28. Ishikawa H., Ziff M. Electron microscopic observations of immunoreactive cells in the rheumatoid synovial membrane. Arthritis Rheum. 1976 Jan-Feb;19(1):1–14. doi: 10.1002/art.1780190101. [DOI] [PubMed] [Google Scholar]
  29. Keizer G. D., Borst J., Figdor C. G., Spits H., Miedema F., Terhorst C., De Vries J. E. Biochemical and functional characteristics of the human leukocyte membrane antigen family LFA-1, Mo-1 and p150,95. Eur J Immunol. 1985 Nov;15(11):1142–1148. doi: 10.1002/eji.1830151114. [DOI] [PubMed] [Google Scholar]
  30. Laffon A., Sánchez-Madrid F., Ortíz de Landázuri M., Jiménez Cuesta A., Ariza A., Ossorio C., Sabando P. Very late activation antigen on synovial fluid T cells from patients with rheumatoid arthritis and other rheumatic diseases. Arthritis Rheum. 1989 Apr;32(4):386–392. doi: 10.1002/anr.1780320405. [DOI] [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. Phillips D. R., Charo I. F., Parise L. V., Fitzgerald L. A. The platelet membrane glycoprotein IIb-IIIa complex. Blood. 1988 Apr;71(4):831–843. [PubMed] [Google Scholar]
  34. 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]
  35. Pitzalis C., Kingsley G., Murphy J., Panayi G. Abnormal distribution of the helper-inducer and suppressor-inducer T-lymphocyte subsets in the rheumatoid joint. Clin Immunol Immunopathol. 1987 Nov;45(2):252–258. doi: 10.1016/0090-1229(87)90040-7. [DOI] [PubMed] [Google Scholar]
  36. Pulido R., Cebrián M., Acevedo A., de Landázuri M. O., Sánchez-Madrid F. Comparative biochemical and tissue distribution study of four distinct CD45 antigen specificities. J Immunol. 1988 Jun 1;140(11):3851–3857. [PubMed] [Google Scholar]
  37. 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]
  38. Scott D. L., Wainwright A. C., Walton K. W., Williamson N. Significance of fibronectin in rheumatoid arthritis and osteoarthrosis. Ann Rheum Dis. 1981 Apr;40(2):142–153. doi: 10.1136/ard.40.2.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Shaw L. M., Messier J. M., Mercurio A. M. The activation dependent adhesion of macrophages to laminin involves cytoskeletal anchoring and phosphorylation of the alpha 6 beta 1 integrin. J Cell Biol. 1990 Jun;110(6):2167–2174. doi: 10.1083/jcb.110.6.2167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Spits H., Yssel H., Leeuwenberg J., De Vries J. E. Antigen-specific cytotoxic T cell and antigen-specific proliferating T cell clones can be induced to cytolytic activity by monoclonal antibodies against T3. Eur J Immunol. 1985 Jan;15(1):88–91. doi: 10.1002/eji.1830150117. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Sánchez-Madrid F., De Landázuri M. O., Morago G., Cebrián M., Acevedo A., Bernabeu C. VLA-3: a novel polypeptide association within the VLA molecular complex: cell distribution and biochemical characterization. Eur J Immunol. 1986 Nov;16(11):1343–1349. doi: 10.1002/eji.1830161106. [DOI] [PubMed] [Google Scholar]
  44. Sánchez-Mateos P., Cebrián M., Acevedo A., López-Botet M., De Landázuri M. O., Sánchez-Madrid F. Expression of a gp33/27,000 MW activation inducer molecule (AIM) on human lymphoid tissues. Induction of cell proliferation on thymocytes and B lymphocytes by anti-AIM antibodies. Immunology. 1989 Sep;68(1):72–79. [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. 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]
  47. Wright S. D., Levin S. M., Jong M. T., Chad Z., Kabbash L. G. CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide. J Exp Med. 1989 Jan 1;169(1):175–183. doi: 10.1084/jem.169.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ziff M. Role of endothelium in chronic inflammation. Springer Semin Immunopathol. 1989;11(2):199–214. doi: 10.1007/BF00197189. [DOI] [PubMed] [Google Scholar]

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