Production of Cytokines and Metalloproteinases in Rheumatoid Synovitis Is T Cell Dependent

In rheumatoid arthritis, T lymphocytes have been proposed to play a pivotal role in the disease process, but they have also been considered to simply represent an epiphenomenon in a primarily synoviocyte/macrophage-driven disease. To directly examine the contribution of CD4 T cells in synovitis, T cells were either depleted from or adoptively transferred into NOD-SCID mice engrafted with rheumatoid synovial tissue. Injection of anti-CD2 antibody resulted in the elimination of 80–90% of tissue-infiltrating T cells in the synovial grafts and was followed by a marked decline in the production of IL-1β (loss of 70%), TNF-α (loss of 86%), and IL-15 (loss of 84%) mRNA. Also, transcription of MMP-1 and MMP-2 was reduced by 72% in anti-CD2-treated chimeras. Immunohistochemistry demonstrated that the cytokines and proteases derived mostly from CD68+synovial cells, which disappeared from the tissue upon T cell depletion. Adoptive transfer of autologous tissue-derived T cell lines and T cell clones into synovium–SCID mouse chimeras augmented the production of IFN-γ as well as TNF-α in the synovial infiltrates. Administration of IFN-γ in small doses to anti-CD2-treated chimeras restored the survival and the functional activity of CD68+synovial cells.In vitrostudies confirmed the critical role of synovial T cells and IFN-γ in the survival of synovial CD68+cells. These data demonstrate that the production of proinflammatory cytokines and of tissue-degrading enzymes in rheumatoid synovitis is T cell dependent and that CD4 T cells are primary regulatory cells in this disease.