title: 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.
abstract: OBJECTIVE
  Resistance of Teff cells to Treg cell-mediated suppression contributes to the breakdown of peripheral tolerance in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). However, unanswered questions are whether this resistant phenotype is self-sustained and whether CD8+ and CD4+ Teff cells share the same mechanism of resistance to suppression. We undertook this study to investigate intrinsic resistance of CD8+ Teff cells to suppression and to determine how this can be targeted therapeutically.
  
  
  METHODS
  CD8+ or CD4+ Teff cells were cultured with or without antigen-presenting cells (APCs) in Treg cell-dependent and -independent suppression assays. Synovial fluid (SF)-derived Teff cells were crosscultured with peripheral blood (PB) Treg cells from JIA patients or healthy controls. Tumor necrosis factor (TNF) or interferon-γ (IFNγ) blocking agents were used to restore Teff cell responsiveness to suppression.
  
  
  RESULTS
  Suppression of cell proliferation and cytokine production in CD8+ Teff cells from the SF of JIA patients was severely impaired compared to that in CD8+ Teff cells from the PB of JIA patients, regardless of the presence of APCs and CD4+ Teff cells. Similar to CD4+ Teff cells, impaired suppression of CD8+ Teff cells was shown to be an intrinsic feature of this cell population. While TNF blockade restored both CD8+ and CD4+ Teff cell susceptibility to suppression, autocrine release of IFNγ selectively sustained CD8+ Teff cell resistance, which could be relieved by IFNγ blockade.
  
  
  CONCLUSIONS
  Unlike CD4+ Teff cells, resistance of CD8+ Teff cells to suppression at the site of autoimmune inflammation is maintained by autocrine release of IFNγ, and blockade of IFNγ restores CD8+ Teff cell responsiveness to suppression. These findings indicate a potential therapeutic value of blocking IFNγ to restore immune regulation in JIA.
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Petrelli
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Wehrens
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rianne C
authors.initials: RC
authors.lastname: Scholman
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Berent J
authors.initials: BJ
authors.lastname: Prakken
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Vastert
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
mesh_terms: D000293:Adolescent; D000938:Antigen-Presenting Cells; D001171:Arthritis, Juvenile / Q000276:immunology*; D001327:Autoimmune Diseases; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D013582:Synovial Fluid / Q000166:cytology; D050378:T-Lymphocytes, Regulatory; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D015850:Interleukin-6; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma