Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

CD8+ T cells in human autoimmune arthritis: the unusual suspects

Nature Reviews Rheumatology volume 12, pages 421–428 (2016)Cite this article

Subjects

Key Points

  • CD8+ T-cell homeostasis is altered in the peripheral blood of patients with autoimmune arthritis

  • The close association of MHC class I polymorphisms with disease risk and the correlation of CD8+ T-cell number with disease outcome support the idea that this cell population has a role in autoimmune arthritis

  • At sites of chronic inflammation, the phenotype of CD8+ T cells is heterogeneous and includes proinflammatory and anti-inflammatory features

  • In inflammatory environments, CD8+ T cells lose susceptibility to regulation, and this loss is sustained by autocrine release of proinflammatory cytokines

  • Subsets of memory CD8+ T cells upregulate negative costimulatory markers and either develop an exhausted phenotype or display a tissue-instructed differentiation, as in tissue-resident memory T cells

Abstract

CD8+ T cells are key players in the body's defence against viral infections and cancer. To date, data on the role of CD8+ T cells in autoimmune diseases have been scarce, especially when compared with the wealth of research on CD4+ T cells. However, growing evidence suggests that CD8+ T-cell homeostasis is impaired in human autoimmune diseases. The contribution of CD8+ T cells to autoimmune arthritis is indicated by the close association of MHC class I polymorphisms with disease risk, as well as the correlation between CD8+ T-cell phenotype and disease outcome. The heterogeneous phenotype, resistance to regulation and impaired regulatory function of CD8+ T cells — especially at the target organ — might contribute to the persistence of autoimmune inflammation. Moreover, newly identified populations of tissue-resident CD8+ T cells and their interaction with antigen-presenting cells might have a key role in disease pathology. In this Review, we assess the link between CD8+ T cells, autoimmune arthritis and the basis of their homeostatic changes under inflammatory conditions. Improved insight into CD8+ T cell-specific pathogenicity will be essential for a better understanding of autoimmune arthritis and the identification of new therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CD8+ T-cell differentiation in autoimmune inflammation.
Figure 2: CD8+ T-cell regulation in autoimmune arthritis.

Similar content being viewed by others

References

  1. Palmer, M. T. & Weaver, C. T. Autoimmunity: increasing suspects in the CD4+ T cell lineup. Nat. Immunol. 11, 36–40 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Gravano, D. M. & Hoyer, K. K. Promotion and prevention of autoimmune disease by CD8+ T cells. J. Autoimmun. 45, 68–79 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Brewerton, D. A. et al. Ankylosing spondylitis and HLA 27. Lancet 1, 904–907 (1973).

    Article  CAS  PubMed  Google Scholar 

  4. Brown, M. A., Kenna, T. & Wordsworth, B. P. Genetics of ankylosing spondylitis-insights into pathogenesis. Nat. Rev. Rheumatol. 12, 81–91 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Evans, D. M. et al. Interaction between ERAP1 and HLAB27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLAB27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cortes, A. et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat. Commun. 6, 7146 (2015).

    Article  PubMed  Google Scholar 

  7. Bowes, J. et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat. Commun. 6, 6046 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hollenbach, J. A. et al. Juvenile idiopathic arthritis and HLA class I and class II interactions and ageatonset effects. Arthritis Rheum. 62, 1781–1791 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hinks, A. et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat. Genet. 45, 664–669 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ombrello, M. J. et al. HLADRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc. Natl Acad. Sci. USA 115, 15970–15975 (2015).

    Article  CAS  Google Scholar 

  12. Coulthard, L. R. et al. Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients. Clin. Exp. Immunol. 170, 36–46 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Carvalheiro, H., Duarte, C., Silva-Cardoso, S., da Silva, J. A. & Souto-Carneiro, M. M. CD8+ T cell profiles in patients with rheumatoid arthritis and their relationship to disease activity. Arthritis Rheumatol. 67, 363–371 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Li, S. et al. Expression of programmed death1 (PD1) on CD4+ and CD8+ T cells in rheumatoid arthritis. Inflammation 37, 116–121 (2014).

    Article  PubMed  CAS  Google Scholar 

  15. Liu, Y. et al. Increased Tim3 expression on peripheral lymphocytes from patients with rheumatoid arthritis negatively correlates with disease activity. Clin. Immunol. 137, 288–295 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Costello, P., Bresnihan, B., O'Farrelly, C. & FitzGerald, O. Predominance of CD8+ T lymphocytes in psoriatic arthritis. J. Rheumatol. 26, 1117–1124 (1999).

    CAS  PubMed  Google Scholar 

  17. Hunter, P. J. et al. Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression. Arthritis Rheum. 62, 896–907 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cho, B. A. et al. Characterization of effector memory CD8+ T cells in the synovial fluid of rheumatoid arthritis. J. Clin. Immunol. 32, 709–720 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Romio, M. et al. Extracellular purine metabolism and signaling of CD73derived adenosine in murine Treg and Teff cells. Am. J. Physiol. Cell Physiol. 301, C530–C539 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Botta Gordon-Smith, S., Ursu, S., Eaton, S., Moncrieffe, H. & Wedderburn, L. R. Correlation of low CD73 expression on synovial lymphocytes with reduced adenosine generation and higher disease severity in juvenile idiopathic arthritis. Arthritis Rheumatol. 67, 545–554 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kohlmann, W. M., Urban, W., Sterry, W. & Foerster, J. Correlation of psoriasis activity with abundance of CD25+CD8+ T cells: conditions for cloning T cells from psoriatic plaques. Exp. Dermatol. 13, 607–612 (2004).

    Article  PubMed  Google Scholar 

  22. Menon, B. et al. Interleukin17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol. 66, 1272–1281 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Borgato, L. et al. The T cell receptor repertoire in psoriatic synovitis is restricted and T lymphocytes expressing the same TCR are present in joint and skin lesions. J. Rheumatol. 29, 1914–1919 (2002).

    CAS  PubMed  Google Scholar 

  26. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Vukmanovic-Stejic, M., Vyas, B., Gorak-Stolinska, P., Noble, A. & Kemeny, D. M. Human Tc1 and Tc2/Tc0 CD8 Tcell clones display distinct cell surface and functional phenotypes. Blood 95, 231–240 (2000).

    CAS  PubMed  Google Scholar 

  28. Yen, H. R. et al. Tc17 CD8 T cells: functional plasticity and subset diversity. J. Immunol. 183, 7161–7168 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Liu, Y. et al. Interleukin21 induces the differentiation of human Tc22 cells via phosphorylation of signal transducers and activators of transcription. Immunology 132, 540–548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Luan, L., Ding, Y., Han, S., Zhang, Z. & Liu, X. An increased proportion of circulating Th22 and Tc22 cells in psoriasis. Cell. Immunol. 290, 196–200 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Ortega, C. et al. IL17producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17related cytokines. J. Leukoc. Biol. 86, 435–443 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Kirkham, B. W., Kavanaugh, A. & Reich, K. Interleukin17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. Immunology 141, 133–142 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Prezzemolo, T. et al. Functional signatures of human CD4 and CD8 T cell responses to Mycobacterium tuberculosis. Front. Immunol. 5, 180 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Li, S. et al. Expression of TIM3 on CD4+ and CD8+ T cells in the peripheral blood and synovial fluid of rheumatoid arthritis. APMIS 122, 899–904 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Kang, Y. M. et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J. Exp. Med. 195, 1325–1336 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Harada, S. et al. Production of interleukin7 and interleukin15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 42, 1508–1516 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. McInnes, I. B. et al. The role of interleukin15 in T cell migration and activation in rheumatoid arthritis. Nat. Med. 2, 175–182 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Fitzgerald, J. E. et al. Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis. J. Immunol. 154, 3538–3547 (1995).

    CAS  PubMed  Google Scholar 

  39. Hingorani, R. et al. Oligoclonality of V beta 3 TCR chains in the CD8+ T cell population of rheumatoid arthritis patients. J. Immunol. 156, 852–858 (1996).

    CAS  PubMed  Google Scholar 

  40. Hall, F. C., Thomson, K., Procter, J., McMichael, A. J. & Wordsworth, B. P. TCRβ spectratyping in RA: evidence of clonal expansions in peripheral blood lymphocytes. Ann. Rheum. Dis. 57, 319–322 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fazou, C., Yang, H., McMichael, A. J. & Callan, M. F. Epitope specificity of clonally expanded populations of CD8+ T cells found within the joints of patients with inflammatory arthritis. Arthritis Rheum. 44, 2038–2045 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Klarenbeek, P. L. et al. Inflamed target tissue provides a specific niche for highly expanded Tcell clones in early human autoimmune disease. Ann. Rheum. Dis. 71, 1088–1093 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187–197 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Iijima, N. & Iwasaki, A. Tissue instruction for migration and retention of TRM cells. Trends Immunol. 36, 556–564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Thome, J. J. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Farber, D. L., Yudanin, N. A. & Restifo, N. P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Clark, R. A. Resident memory T cells in human health and disease. Sci. Transl. Med. 7, 269rv261 (2015).

    Article  CAS  Google Scholar 

  49. Cheuk, S. et al. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J. Immunol. 192, 3111–3120 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Henderson, L. A. et al. Novel 3dimensional explant method facilitates the study of lymphocyte populations in the synovium and reveals a large population of resident memory T cells in rheumatoid arthritis. Arthritis Rheum. 66, S209–S209 (2014).

    Article  Google Scholar 

  51. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD1 and their advantages for clinical application. Nat. Immunol. 14, 1212–1218 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H. & Freeman, G. J. Programmed death1 ligand 1 interacts specifically with the B71 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schneider, H. et al. Reversal of the TCR stop signal by CTLA4. Science 313, 1972–1975 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Francisco, L. M. et al. PDL1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015–3029 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Oderup, C., Cederbom, L., Makowska, A., Cilio, C. M. & Ivars, F. Cytotoxic T lymphocyte antigen-4dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory Tcell-mediated suppression. Immunology 118, 240–249 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sehrawat, S. et al. Galectin9/TIM3 interaction regulates virus-specific primary and memory CD8 T cell response. PLoS Pathog. 6, e1000882 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kim, P. S. & Ahmed, R. Features of responding T cells in cancer and chronic infection. Curr. Opin. Immunol. 22, 223–230 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Speiser, D. E. et al. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat. Rev. Immunol. 14, 768–774 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Wakim, L. M. et al. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J. Immunol. 189, 3462–3471 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Raptopoulou, A. P. et al. The programmed death 1/programmed death ligand 1 inhibitory pathway is upregulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis. Arthritis Rheum. 62, 1870–1880 (2010).

    CAS  PubMed  Google Scholar 

  62. Schneider, A. et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+FOXP3+ regulatory T cells. J. Immunol. 181, 7350–7355 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Schneider, A. et al. In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive Tregs involves IL6mediated signaling. Sci. Transl. Med. 5, 170ra115 (2013).

    Article  CAS  Google Scholar 

  64. Venigalla, R. K. et al. Reduced CD4+,CD25− T cell sensitivity to the suppressive function of CD4+,CD25high, CD127−/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 58, 2120–2130 (2008).

    Article  PubMed  Google Scholar 

  65. Xiao, H. TRAIL is associated with impaired regulation of CD4+CD25− T cells by regulatory T cells in patients with rheumatoid arthritis. J. Clin. Immunol. 6, 1112–1119 (2011).

    Article  CAS  Google Scholar 

  66. Wehrens, E. J. et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/cakt hyperactivation in effector cells. Blood 118, 3538–3548 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Haufe, S. et al. Impaired suppression of synovial fluid CD4+CD25− T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells. Arthritis Rheum. 63, 3153–3162 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Petrelli, A. et al. Self-sustained resistance to suppression of CD8+ Teff cells at the site of autoimmune inflammation can be reversed by tumor necrosis factor and interferon-γ blockade. Arthritis Rheumatol. 68, 229–236 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Wehrens, E. J. et al. Anti-tumor necrosis factor α targets protein kinase B/cAkt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis. Arthritis Rheum. 65, 3279–3284 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Rifa'i, M., Kawamoto, Y., Nakashima, I. & Suzuki, H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J. Exp. Med. 200, 1123–1134 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Moore, J. S. & Calkins, C. E. In vitro regulation of the pathogenic autoantibody response of New Zealand black mice. I. Loss with age of suppressive activity in T cell populations. J. Immunol. 134, 3838–3844 (1985).

    CAS  PubMed  Google Scholar 

  72. Notley, C. A., McCann, F. E., Inglis, J. J. & Williams, R. O. ANTICD3 therapy expands the numbers of CD4+ and CD8+ Treg cells and induces sustained amelioration of collagen-induced arthritis. Arthritis Rheum. 62, 171–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Yamaguchi, T., Wing, J. B. & Sakaguchi, S. Two modes of immune suppression by Foxp3+ regulatory T cells under inflammatory or non-inflammatory conditions. Seminars Immunol. 23, 424–430 (2011).

    Article  CAS  Google Scholar 

  74. Li, S. et al. A naturally occurring CD8+CD122+ Tcell subset as a memory-like Treg family. Cell. Mol. Immunol. 11, 326–331 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cosmi, L. et al. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 102, 4107–4114 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Ceeraz, S., Hall, C., Choy, E. H., Spencer, J. & Corrigall, V. M. Defective CD8+CD28− regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy. Clin. Exp. Immunol. 174, 18–26 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ellis, S. D. et al. Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor α and CD86. Arthritis Rheumatol. 66, 2694–2705 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Boltjes, A. & van Wijk, F. Human dendritic cell functional specialization in steady-state and inflammation. Front. Immunol. 5, 131 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Ziegler-Heitbrock, L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J. Leukoc. Biol. 81, 584–592 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Thomas, R. & Quinn, C. Functional differentiation of dendritic cells in rheumatoid arthritis: role of CD86 in the synovium. J. Immunol. 156, 3074–3086 (1996).

    CAS  PubMed  Google Scholar 

  82. Moret, F. M. et al. Intra-articular CD1cexpressing myeloid dendritic cells from rheumatoid arthritis patients express a unique set of T cell-attracting chemokines and spontaneously induce Th1, Th17 and Th2 cell activity. Arthritis Res. Ther. 15, R155 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Jongbloed, S. L. et al. Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis. Arthritis Res. Ther. 8, R15 (2006).

    Article  PubMed  CAS  Google Scholar 

  84. Kawanaka, N. et al. CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis. Arthritis Rheum. 46, 2578–2586 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Yoon, B. R. et al. Functional phenotype of synovial monocytes modulating inflammatory Tcell responses in rheumatoid arthritis (RA). PLoS ONE 9, e109775 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Jongbloed, S. L. et al. Human CD141+ (BDCA3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247–1260 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kassianos, A. J., Jongbloed, S. L., Hart, D. N. & Radford, K. J. Isolation of human blood DC subtypes. Methods Mol. Biol. 595, 45–54 (2010).

    Article  PubMed  Google Scholar 

  88. Kurts, C. et al. Constitutive class Irestricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923–930 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Schreibelt, G. et al. The Ctype lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood 119, 2284–2292 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Haniffa, M. et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37, 60–73 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Smolewska, E. et al. Distribution and clinical significance of blood dendritic cells in children with juvenile idiopathic arthritis. Ann. Rheum. Dis. 67, 762–768 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Prakken, B., Albani, S. & Martini, A. Juvenile idiopathic arthritis. Lancet 377, 2138–2149 (2011).

    Article  PubMed  Google Scholar 

  93. Sakkas, L. I., Bogdanos, D. P., Katsiari, C. & Platsoucas, C. D. Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment. Autoimmun. Rev. 13, 1114–1120 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Bulatovic Calasan, M. et al. Methotrexate treatment affects effector but not regulatory T cells in juvenile idiopathic arthritis. Rheumatology 54, 1724–1734 (2015).

    Article  PubMed  CAS  Google Scholar 

  95. Aravena, O. et al. Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets. Immunobiology 216, 1256–1263 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Scarsi, M. et al. Reduction of peripheral blood T cells producing IFN-γ and IL17 after therapy with abatacept for rheumatoid arthritis. Clin. Exp. Rheumatol. 32, 204–210 (2014).

    CAS  PubMed  Google Scholar 

  97. Melet, J. et al. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum. 65, 2783–2790 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLAB and HLAA. Nature 450, 887–892 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Coppieters, K. T. et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J. Exp. Med. 209, 51–60 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Unger, W. W. et al. Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLAA2 transgenic NOD/scid/IL2RG null mice. PLoS ONE 7, e49213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Skulina, C. et al. Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc. Natl Acad. Sci. USA 101, 2428–2433 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Crawford, M. P. et al. High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood 103, 4222–4231 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. McKinney, E. F. et al. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat. Med. 16, 586–591 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. & Smith, K. G. Tcell exhaustion, costimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

A.P. is supported by the European Union Seventh Framework Programme (501100004963, 289903). F.V.W. is supported by the VIDI grant from the Netherlands Organization for Scientific Research (NWO, ZonMW) and by the Dutch Arthritis Foundation Reumafonds

Author information

Authors and Affiliations

  1. Laboratory of Translational Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Lundlaan 6, Utrecht, 3508 AB, Netherlands

    Alessandra Petrelli & Femke van Wijk

Authors
  1. Alessandra Petrelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Femke van Wijk
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.P. researched data for the article and wrote the manuscript. F.V.W. reviewed and edited the manuscript before submission. A.P. and F.V.W. contributed equally to discussions of the content.

Corresponding author

Correspondence to Femke van Wijk.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Petrelli, A., van Wijk, F. CD8+ T cells in human autoimmune arthritis: the unusual suspects. Nat Rev Rheumatol 12, 421–428 (2016). https://doi.org/10.1038/nrrheum.2016.74

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2016.74

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing