Effector Function of Resting T Cells: Activation of Synovial Fibroblasts

Abstract

Synovial tissue in rheumatoid arthritis is characterized by infiltration with large numbers of T lymphocytes and APCs as well as hyperplasia of synovial fibroblasts. Current understanding of the pathogenesis of RA includes the concept that synovial fibroblasts, which are essential to cartilage and bone destruction, are regulated by cytokines derived primarily from monocyte-macrophage cells. Recently it has been found that synovial fibroblasts can also function as accessory cells for T cell activation by superantigens and other stimuli. We have now found that highly purified resting T cells, even in the absence of T cell mitogens, induce activation of synovial fibroblasts when cocultured for 6–24 h. Such activation was evident by induction or augmentation of mRNA for stromelysin, IL-6, and IL-8, gene products important in joint inflammation and joint destruction. Furthermore, increased production of IL-6 and IL-8 was quantitated by intracellular cytokine staining and flow cytometry. This technique, previously used for analysis of T cell function, was readily adaptable for assays of synovial fibroblasts. Resting T cells also induced synovial fibroblasts to produce PGE2, indicating activation of expression of the cyclooxygenase 2 gene. Synergy was observed between the effects of IL-17, a cytokine derived from stimulated T cells that activates fibroblasts, and resting T lymphocytes. Various subsets of T cells, CD4+, CD8+, CD45RO+, and CD45RA+ all had comparable ability to induce synovial fibroblast activation. These results establish an Ag-independent effector function for resting T cells that is likely to be important in inflammatory compartments in which large numbers of T lymphocytes and fibroblasts can come into direct contact with each other.

Augmented production of chemokines by the interaction of type II collagen–reactive T cells with rheumatoid synovial fibroblasts

“…We found that the production of IL-8, MCP-1, and MIP-1␣ was significantly augmented when FLS were cocultured with CIIstimulated T cells. Recently, Yamamura et al demonstrated that resting T cells, even in the absence of T cell mitogens or antigens, could induce activation of FLS when cocultured (36). In the present study, although the production of chemokines from FLS was slightly increased by interaction with resting T cells, it was augmented much more by interaction with CII-stimulated T cells.…”

Synovial biology and T cells in rheumatoid arthritis

“…Using resting T cells as a stimulus, we have documented activation of FLS and release of proinflammatory mediators [13]. We found that autologous or allogeneic resting T cells have similar activating potential on FLS.…”

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

“…PGE 2 , which can be produced by fibroblasts, was shown to have anti-proliferative effects on T lymphocytes and to decrease IFN-γ levels, but more recent evidence has shown that PGE 2 augments T H 17 cell differentiation [119] and this may serve as another pathway by which fibroblasts could contribute to inflammatory disorders. Conversely, IL-17A has been shown to cause an increase in fibroblast PGE 2 production [120].…”