Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (40), p.16717-16722
• Main Authors: Beavis, Paul A, Gregory, Bernard, Green, Patricia, Cribbs, Adam P, Kennedy, Alan, Amjadi, Parisa, Palfreeman, Andrew C, Feldmann, Marc, Brennan, Fionula M
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - immunology; Biological Sciences; Cell activation; Cell culture; CTLA-4 protein; cultured cells; Cytokines; Flow Cytometry; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene expression; Humans; Immunoregulation; Inflammatory diseases; Interleukin 2; Interleukin 6; Joint Capsule - cytology; Joint Capsule - immunology; Joint Capsule - metabolism; Lentivirus; LFA-1 antigen; Luciferases; Lymphocytes T; macrophage activation; Macrophages; NF- Kappa B protein; NF-kappa B - immunology; NF-kappa B - metabolism; Rheumatoid arthritis; Rodents; Synovium; T cell receptors; T-lymphocytes; T-Lymphocytes, Regulatory - immunology; Transduction, Genetic; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1112722108

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.