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The role of interleukin–15 in T–cell migration and activation in rheumatoid arthritis

Nature Medicinevolume 2pages175182 (1996) | Download Citation



Interleukin 15 (IL–15) is a novel cytokine with interleukin–2–like activity. It is also a potent T–lymphocyte chemoattractant. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the presence of activated T lymphocytes, macrophages and synoviocytes in the synovial membrane. The mechanisms of T–cell activation in RA are currently unclear. We report the presence of high concentrations of IL–15 in rheumatoid arthritis (RA) synovial fluid and have demonstrated its expression in the synovial membrane lining layer by immunohistochemistry. RA synovial fluids were found to contain chemotactic activity, which was attributable in part to the presence of IL–15. Moreover, in a murine model, injection of recombinant IL–15 was found to induce a local tissue inflammatory infiltrate consisting predominantly of T lymphocytes. Synovial fluid T lymphocytes proliferate in response to IL–15, demonstrating that continued responsiveness to IL–15 is a feature of T cells after entry into the synovial compartment. These data suggest that IL–15 can recruit and activate T lymphocytes into the synovial membrane, thereby contributing to RA pathogenesis.

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  1. 1

    Grabstein, K.H. et al. Cloning of a T cell growth factor that interacts with the β-chain of the interleukin-Z receptor. Science 264, 965–967 (1994).

  2. 2

    Girl, J.G. et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the α chain of the IL-2 receptor. EMBO J. 14. 3654–3663 (1995).

  3. 3

    Burton, J.D. et al. A lymphokine, provisionally designated interleukin T and produced by a human adult T cell leukemia line, stimulates T cell proliferation and the induction of lymphokine-activated killer cells. Proc. Natl. Acad. Sci. USA 91, 4935–4939 (1994).

  4. 4

    Bamford, R.N. et al. The interleukin (IL) 2 receptor β-chain is shared by IL-2 and a cytokine provisionally designated IL-T, that stimulates T cell proliferation and the induction of lymphokine activated killer cells. Proc. Natl. Acad. Sci. USA 91, 4940–4944 (1994).

  5. 5

    Giri, J.G. et al. Utilization of the b and g chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 13. 2822–2830 (1994).

  6. 6

    Carson, W.E. et al. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J. Exp. Med. 180, 1395–1403 (1994).

  7. 7

    Armitage, R.J., MacDuff, B.M., Eisenman, J., Paxton, R. & Grabstein, K.H. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J. Immunol. 154, 483–490 (1995).

  8. 8

    Wilkinson, P.C. & Liew, F.Y. Chemoattraction of human blood T lymphocytes by IL-15. J. Exp. Med. 181, 1255–1259 (1995).

  9. 9

    Maini, R.N., Chu, C.A. & Feldmann, M. Aetiopathogenesis of rheumatoid arthritis, in Mechanisms and Models in Rheumatoid Arthritis (eds Henderson, B., Edwards, J.C.W. & Pettipher, E.R.) 25–26 (Academic Press, London, 1995).

  10. 10

    Duke, O., Panayi, G.S., Janossy, G. & Poulter, L. An immunohistochemical analysis of lymphocyte subpopulations and their microenvironment in the synovial membrane of patients with rheumatoid arthritis using monoclonal antibodies. Clin. Exp. Immunol 49, 22–30 (1982).

  11. 11

    Field, M., Chu, C., Feldmann, M. & Maini, R.N. Interleukin-6 localisation in rheumatoid arthritis synovial membrane. Rheum. Int. 11, 45–50 (1991).

  12. 12

    Deleuran, B.W. et al Localization of interleukin-α receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage-pannus junction in rheumatoid arthritis. Br. J. Rheumatol. 31, 801–809 (1991).

  13. 13

    Deleuran, B. et al Localization of IL-8 in the synovial membrane, cartilage-pan-nus junction and chondrocyte in rheumatoid arthritis. Scand. J. Rheumatol 23 2–7 (1994).

  14. 14

    Chu, C., Field, M., Feldmann, M. & Maini, R.N. Localisation of tumour necrosis factor alpha in synovial tissue and at the cartilage-pannus junction in rheumatoid arthritis. Arthritis Rheum. 34, 1125–1132 (1991).

  15. 15

    Chu, C.G. et al. Detection of cytokines at the cartilage pannus junction in patiens with rheumatoid arthitis: Implications for the role of cytokines in in cartilage destruction and repair. BR. J. Rheumatol. 31 653–661 (1992).

  16. 16

    Thomas, R., Mcllraith, M., Davis, L.S. & Lipsky, P.E. Rheumatoid synovium is enriched in CD45RBdim mature memory T cells that are potent helpers for B cell differentiation. Arthritis Rheum. 35, 1455–1465 (1992).

  17. 17

    lannone, F., Corrigall, V.M., Kingsley, G. & Panayi, G. Evidence for continuous recruitment and activation of T cells into the joints of patients with rheumatoid arthritis. Eur. J. Immunol. 24, 2706–2713. (1994)

  18. 18

    Horneff, G., Burmeister, G.R., Emmrich, F. & Kalden, J.R. Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody. Arth. Rheum. 34, 129–140 (1991).

  19. 19

    Wendling, D., Wijdenes, J., Racadot, E. & Morel-Fourrier, B. Therapeutic use of monoclonal anti-CD4 antibody in rheumatoid arthritis. J. Rheumatol. 18, 325–327 (1991).

  20. 20

    Harrison, W.B., Cyclosporin. in Second-line Agents in the Treatment of Rheumatic Diseases (eds Dixon, J.S. & Furst, D.E.) (Dekker, New York, 1992).

  21. 21

    Simon, K., Seipelt, E. & Sieper, J. Divergent T cell cytokine patterns in inflammatory arthritis. Proc. Natl. Acad. Sci. USA 91, 8562–8566 (1994).

  22. 22

    Ulfgren A.-K. ., Lindblad, S., KlaresKog, L., Andersson, J. & Andersson, U. Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis. Ann. Rheum. Dis. 54, 654–661 (1995).

  23. 23

    Firestein, G. et al. Cytokines in chronic inflammatory arthritis. Failure to detect T cell lymphokines (IL-2 and IL-3) and presence of macrophage colony stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovi-tis. J. Exp. Med. 168, 1573–1586 (1988).

  24. 24

    Firestein, G. & Zvaifler, N. Peripheral blood and synovial fluid monocyte activation in inflammatory synovitis. II. Low levels of synovial fluid and synovial tissue interferon suggest that y-interferon is not the primary macrophage activating factor. Arthritis Rheum. 30, 864–871 (1987).

  25. 25

    Firestein, G.S. & Zwaifler, N.J. How important are T cells in chronic rheumatoid synovitis. Arthritis Rheum. 33, 768–773 (1990).

  26. 26

    Panayi, G.S., Lanchbury, J.S. & Kingsley, G.H. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 35, 729–735. (1992).

  27. 27

    Koch, A.E. et al. Synovial tissue macrophages as a source of the chemotactic cytokine IL-8. J. Immunol. 147, 2187–2195 (1991).

  28. 28

    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 MlP-lα and MIP-1β. Science 260, 355–358 (1993).

  29. 29

    Wilkinson/P, C. The locomotor capacity of human lymphocytes and its enhancement by cell growth. Immunology 57, 281–287 (1986).

  30. 30

    Duff, G.W. Cytokines and anti-cytokines. Br. J. Rheumatol. 32 (Suppl 1), 15–20 (1993).

  31. 31

    Brennan, F.M., Field, M., Feldmann, M. & Maini, R.N. Cytokine expression in rheumatoid arthritis. Br. J. Rheum. 30 (Suppl 2), 75–80 (1991).

  32. 32

    Burmester, G. et al. Differential expression of la antigens by rheumatoid synovial lining cells. J. Clin. Invest. 80, 595–604 (1987).

  33. 33

    Pitzalis C., Kingsley, G., Lanchbury, J.S.S., Murphy, J. . & Panayi, G.S. Expression of HLA-DR, DQ, and DP antigens and interleukin 2 receptor on synovial fluid T lymphocytes subsets in rheumatoid arthritis: Evidence of frustrated activation. J. Rheumatol. 14, 662–666 (1987).

  34. 34

    Fernandez-Gutierrez, B., Hernandez-Garcia, C., Banares, A.A. & Jover, J.A. Characterisation and regulation of CD69 expression on rheumatoid arthritis synovial fluid T cells. J. Rheumatol. 22, 413–420 (1995).

  35. 35

    Laffon, A. et al. Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis. J. Clin. Invest. 88. 546–552 (1991).

  36. 36

    Combe, B. et al. Interleukin-2 in rheumatoid arthritis: Production of and response to interleukin-2 in rheumatoid synovial fluid, synovial tissue and peripheral blood. Clin. Exp. Immunol. 59, 520–528 (1985).

  37. 37

    Janeway, C.A. & Bottomley, K. Signals and signs for lymphocyte responses. Cell 76, 275–285 (1994).

  38. 38

    Arnett, F.C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

  39. 39

    Altman, R. et al. Development of criteria for the classification of osteoarthritis: Classification of osteoarthritis of the knee. Arthritis Rheum. 29, 1039–1049 (1986).

  40. 40

    Haston, W.S. & Shields, J.M. Neutrophil leucocyte chemotaxis: A simplified assay for measuring polarising responses to chemotactic factors. J. Immunol. Methods. 81, 229–237 (1985).

  41. 41

    Zigmond, S.H. & Hirsch, J.G. Leukocyte locomotion and chemotaxis. New methods for evaluation and demonstration of a cell derived chemotactic factor. J. Exp. Med. 137, 387–410 (1973).

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  1. Department of Immunology, University Department of Medicine, University of Glasgow, Glasgow, Gl1 6NT, UK

    • Iain B. McInnes
    • , Jamil Al-Mughales
    • , Bernard P. Leung
    • , Fang-ping Huang
    • , Peter C. Wilkinson
    •  & Foo Y. Liew
  2. Centre for Rheumatic Diseases, University Department of Medicine, University of Glasgow, Glasgow, Gl1 6NT, UK

    • Iain B. McInnes
    • , Max Field
    •  & Roger D. Sturrock
  3. Yamanouchi Research Institute, Littlemore Hospital, Oxford, OX4 4XN, UK

    • Richard Dixon


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