title: Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells.
abstract: Increasing evidence suggests that regulatory T cell (Treg) function is impaired in chronic inflammatory diseases such as rheumatoid arthritis (RA). Here we demonstrate that Tregs are unable to modulate the spontaneous production of TNF-α from RA synovial cells cultured from the diseased synovium site. Cytokine (IL-2, IL-6, TNF-α) activated T cells (Tck), cells we previously demonstrated to mimic the effector function of pathogenic RA synovial T cells, contained Tregs that survived and divided in this cytokine environment; however, the up-regulation of key molecules associated with Treg function (CTLA-4 and LFA-1) was impaired. Furthermore, Tregs were unable to suppress the function of Tcks, including contact-dependent induction of TNF-α from macrophages, supporting the concept that impaired Treg function/responsiveness contributes to chronicity of RA. However, ectopic foxp3 expression in both Tcks and pathogenic RA synovial T cells attenuated their cytokine production and function, including contact-dependent activation of macrophages. This diminished response to cytokine activation after ectopic foxp3 expression involved inhibited NF-κB activity and differed mechanistically from that displayed endogenously in conventional Tregs. These results suggest that diseases such as RA may perpetuate owing to the inability of Tregs to control cytokine-activated T-cell function. Understanding the mechanism whereby foxp3 attenuates the pathogenic function of synovial T cells may provide insight into the mechanisms of chronicity in inflammatory disease and potentially reveal new therapeutic candidates.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, London W6 8LH, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.forename: Bernard
authors.initials: B
authors.lastname: Gregory
authors.forename: Patricia
authors.initials: P
authors.lastname: Green
authors.forename: Adam P
authors.initials: AP
authors.lastname: Cribbs
authors.forename: Alan
authors.initials: A
authors.lastname: Kennedy
authors.forename: Parisa
authors.initials: P
authors.lastname: Amjadi
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Palfreeman
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Fionula M
authors.initials: FM
authors.lastname: Brennan
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D017746:Joint Capsule / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016086:Lentivirus; D008156:Luciferases; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases