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Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis

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Abstract

Little is known about the cellular characteristics of CD8+ T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8+ T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD8+ T cells, mainly CD45RA– effector memory (EM) CD8+ T cells, were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. The synovial EM CD8+ T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas-positive cells were prone to apoptosis. In addition, EM CD8+ T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4+CD8+ T cells and IL-4-producing CD8+ T cells (i.e., Tc2 cells) were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8+ suppressor T (Ts) cells increased significantly in the SF of RA patients. Especially, CD8+ T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8+ T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.

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Abbreviations

RA:

Rheumatoid arthritis

PBMCs:

peripheral mononuclear cells

SFMCs:

synovial fluid mononuclear cells

Tc1:

type 1 CD8+ T cells

Tc2:

type 2 CD8+ T cells

Ts:

CD8+ suppressor T cells

References

  1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–61. Epub 2003/05/16.

    Article  PubMed  CAS  Google Scholar 

  2. Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):204. Epub 2008/04/01.

    Article  PubMed  Google Scholar 

  3. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42. Epub 2007/05/26.

    Article  PubMed  CAS  Google Scholar 

  4. Fox DA. The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 1997;40(4):598–609. Epub 1997/04/01.

    Article  PubMed  CAS  Google Scholar 

  5. Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998;101(4):746–54. Epub 1998/03/21.

    Article  PubMed  CAS  Google Scholar 

  6. Chabaud M, Fossiez F, Taupin JL, Miossec P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol. 1998;161(1):409–14. Epub 1998/07/01.

    PubMed  CAS  Google Scholar 

  7. Keystone E. Treatments no longer in development for rheumatoid arthritis. Ann Rheum Dis. 2002;61 Suppl 2:ii43–5. Epub 2002/10/16.

    PubMed  Google Scholar 

  8. Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y 85 days after the first infusion. Arthritis Rheum. 2002;46(6):1470–9. Epub 2002/07/13.

    Article  PubMed  CAS  Google Scholar 

  9. Itoh N, Imagawa A, Hanafusa T, Waguri M, Yamamoto K, Iwahashi H, et al. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med. 1997;186(4):613–8. Epub 1997/08/18.

    Article  PubMed  CAS  Google Scholar 

  10. Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med. 2001;194(5):669–76. Epub 2001/09/06.

    Article  PubMed  CAS  Google Scholar 

  11. Banerjee S, Webber C, Poole AR. The induction of arthritis in mice by the cartilage proteoglycan aggrecan: roles of CD4+ and CD8+ T cells. Cell Immunol. 1992;144(2):347–57. Epub 1992/10/15.

    Article  PubMed  CAS  Google Scholar 

  12. Jiang H, Zhang SI, Pernis B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science. 1992;256(5060):1213–5. Epub 1992/05/22.

    Article  PubMed  CAS  Google Scholar 

  13. Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol. 2004;5(5):516–23. Epub 2004/04/21.

    Article  PubMed  CAS  Google Scholar 

  14. Colovai AI, Liu Z, Ciubotariu R, Lederman S, Cortesini R, Suciu-Foca N. Induction of xenoreactive CD4+ T-cell anergy by suppressor CD8 + CD28- T cells. Transplantation. 2000;69(7):1304–10. Epub 2000/05/08.

    Article  PubMed  CAS  Google Scholar 

  15. Konya C, Goronzy JJ, Weyand CM. Treating autoimmune disease by targeting CD8(+) T suppressor cells. Expert Opin Biol Ther. 2009;9(8):951–65. Epub 2009/06/16.

    Article  PubMed  CAS  Google Scholar 

  16. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol. 1999;113(5):752–9. Epub 1999/11/26.

    Article  PubMed  CAS  Google Scholar 

  17. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187(1):129–34. Epub 1998/01/31.

    Article  PubMed  CAS  Google Scholar 

  18. Inaoki M, Sato S, Shirasaki F, Mukaida N, Takehara K. The frequency of type 2 CD8+ T cells is increased in peripheral blood from patients with psoriasis vulgaris. J Clin Immunol. 2003;23(4):269–78. Epub 2003/09/10.

    Article  PubMed  Google Scholar 

  19. Gilliet M, Liu YJ. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med. 2002;195(6):695–704. Epub 2002/03/20.

    Article  PubMed  CAS  Google Scholar 

  20. Masuko-Hongo K, Sekine T, Ueda S, Kobata T, Yamamoto K, Nishioka K, et al. Long-term persistent accumulation of CD8+ T cells in synovial fluid of rheumatoid arthritis. Ann Rheum Dis. 1997;56(10):613–21. Epub 1997/12/06.

    Article  PubMed  CAS  Google Scholar 

  21. Hall FC, Thomson K, Procter J, McMichael AJ, Wordsworth BP. TCR beta spectratyping in RA: evidence of clonal expansions in peripheral blood lymphocytes. Ann Rheum Dis. 1998;57(5):319–22. Epub 1998/09/19.

    Article  PubMed  CAS  Google Scholar 

  22. Hingorani R, Monteiro J, Furie R, Chartash E, Navarrete C, Pergolizzi R, et al. Oligoclonality of V beta 3 TCR chains in the CD8+ T cell population of rheumatoid arthritis patients. J Immunol. 1996;156(2):852–8. Epub 1996/01/15.

    PubMed  CAS  Google Scholar 

  23. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. Epub 1988/03/01.

    Article  PubMed  CAS  Google Scholar 

  24. Prevoo ML, Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, Vande Putte LB, Van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8. Epub 1995/01/01.

    Article  PubMed  CAS  Google Scholar 

  25. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708–12. Epub 1999/10/28.

    Article  PubMed  CAS  Google Scholar 

  26. Kim HR, Hong MS, Dan JM, Kang I. Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses. Blood. 2006;107(7):2855–62. Epub 2005/12/17.

    Article  PubMed  CAS  Google Scholar 

  27. Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, et al. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol. 2007;178(7):4112–9. Epub 2007/03/21.

    PubMed  CAS  Google Scholar 

  28. Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec G. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing. 2008;5:6. Epub 2008/07/29.

    Article  PubMed  Google Scholar 

  29. Abe K, Takasaki Y, Ushiyama C, Asakawa J, Fukazawa T, Seki M, et al. Expression of CD80 and CD86 on peripheral blood T lymphocytes in patients with systemic lupus erythematosus. J Clin Immunol. 1999;19(1):58–66. Epub 1999/03/18.

    Article  PubMed  CAS  Google Scholar 

  30. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7. Epub 2005/12/31.

    Article  PubMed  CAS  Google Scholar 

  31. Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008;181(10):6738–46. Epub 2008/11/05.

    PubMed  CAS  Google Scholar 

  32. Griffith TS, Yu X, Herndon JM, Green DR, Ferguson TA. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity. 1996;5(1):7–16. Epub 1996/07/01.

    Article  PubMed  CAS  Google Scholar 

  33. Peng SL. Fas (CD95)-related apoptosis and rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):26–30. Epub 2005/09/15.

    Article  CAS  Google Scholar 

  34. Judge AD, Zhang X, Fujii H, Surh CD, Sprent J. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8(+) T cells. J Exp Med. 2002;196(7):935–46. Epub 2002/10/09.

    Article  PubMed  CAS  Google Scholar 

  35. Kim HR, Hwang KA, Kang I. Dual roles of IL-15 in maintaining IL-7RalphalowCCR7- memory CD8+ T cells in humans via recovering the phosphatidylinositol 3-kinase/AKT pathway. J Immunol. 2007;179(10):6734–40. Epub 2007/11/06.

    PubMed  CAS  Google Scholar 

  36. Vallejo AN, Nestel AR, Schirmer M, Weyand CM, Goronzy JJ. Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity. J Biol Chem. 1998;273(14):8119–29. Epub 1998/05/09.

    Article  PubMed  CAS  Google Scholar 

  37. Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med. 1997;186(9):1407–18. Epub 1997/11/14.

    Article  PubMed  CAS  Google Scholar 

  38. Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, et al. Characterization of CD4(+) CTLs ex vivo. J Immunol. 2002;168(11):5954–8. Epub 2002/05/23.

    PubMed  CAS  Google Scholar 

  39. Alves NL, Arosa FA, van Lier RA. IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells. J Immunol. 2005;175(2):755–62. Epub 2005/07/09.

    PubMed  CAS  Google Scholar 

  40. Vossen MT, Matmati M, Hertoghs KM, Baars PA, Gent MR, Leclercq G, et al. CD27 defines phenotypically and functionally different human NK cell subsets. J Immunol. 2008;180(6):3739–45. Epub 2008/03/07.

    PubMed  CAS  Google Scholar 

  41. Harada S, Yamamura M, Okamoto H, Morita Y, Kawashima M, Aita T, et al. Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 1999;42(7):1508–16. Epub 1999/07/14.

    Article  PubMed  CAS  Google Scholar 

  42. McInnes IB, al-Mughales J, Field M, Leung BP, Huang FP, Dixon R, et al. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996;2(2):175–82. Epub 1996/02/01.

    Article  PubMed  CAS  Google Scholar 

  43. Verwilghen J, Lovis R, De Boer M, Linsley PS, Haines GK, Koch AE, et al. Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. J Immunol. 1994;153(3):1378–85. Epub 1994/08/01.

    PubMed  CAS  Google Scholar 

  44. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8. Epub 2001/02/27.

    Article  PubMed  CAS  Google Scholar 

  45. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45. Epub 2007/02/17.

    Article  PubMed  CAS  Google Scholar 

  46. Vukmanovic-Stejic M, Vyas B, Gorak-Stolinska P, Noble A, Kemeny DM. Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes. Blood. 2000;95(1):231–40. Epub 1999/12/23.

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Dr. Peter E. Lipsky for critical comments on the manuscript and Dr. Kyung-Sang Yu (Clinical Trials Center, Seoul National University Hospital) for support in the recruitment of healthy subjects.

This work was supported in part by National Research Foundation of Korea Grant funded by Korean Government (2011-0006498 to H. Kim), by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs (A090369 and A103001 to H. Kim and A110202 to B. Cho) as well as from the “Cooperative Research Program for Agriculture Science & Technology Development (PJ007492 to H. Kim)” Rural Development Administration, Republic of Korea.

Competing interests

The authors declare that they have no competing interests

Author’s contribution

H. Kim had full access to all of the data in the study and took responsibility for the integrity of the data as well as for manuscripts. B. Cho performed most of the experiments, data analysis, and manuscript preparation. J. Sim, J. Park, H. Kim, W. Yoo, S. Lee, D. Lee, J. Kang, Y. Hwang, W. Lee, E. Lee, and I. Kang participated in study design, data acquisition, and analysis. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Republic of Korea

    Bon-A Cho, Ji Hyun Sim, Dong-Sup Lee, Jae Seung Kang, Young-Il Hwang, Wang Jae Lee & Hang-Rae Kim

  2. Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Republic of Korea

    Ji Ah Park, Hye Won Kim & Eun Bong Lee

  3. Seoul National University Bundang Hospital, 166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi, 463-707, Republic of Korea

    Bon-A Cho

  4. Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Jeonju, Jeonbuk, 561-712, Republic of KOREA

    Wan-Hee Yoo

  5. Department of Microbiology, KonKuk University School of Medicine, Chungju, Chungbuk, 380-701, Republic of Korea

    Seung-Hyun Lee

  6. Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

    Insoo Kang

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  1. Bon-A Cho
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Cho, BA., Sim, J.H., Park, J.A. et al. Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis. J Clin Immunol 32, 709–720 (2012). https://doi.org/10.1007/s10875-012-9674-3

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  • DOI: https://doi.org/10.1007/s10875-012-9674-3

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