Molecular Interactions between T Cells and Fibroblast-Like Synoviocytes

Abstract

The mechanism of fibroblast-like synoviocyte (FLS) transformation into an inflammatory phenotype in rheumatoid arthritis (RA) is not fully understood. FLS interactions with invading leukocytes, particularly T cells, are thought to be a critical component of this pathological process. Resting T cells and T cells activated through the T-cell receptor have previously been shown to induce inflammatory cytokine production by FLS. More recently, a distinct population of T cells has been identified in RA synovium that phenotypically resembles cytokine-activated T (Tck) cells. Using time lapse microscopy, the interactions of resting, superantigen-activated, and cytokine-activated T cells with FLS were visualized. Rapid and robust adhesion of Tck and superantigen-activated T cells to FLS was observed that resulted in flattening of the T cells and a crawling movement on the FLS surface. Tck also readily activated FLS to produce interleukin IL-6 and IL-8 in a cell contact-dependent manner that was enhanced by exogenous IL-17. Although LFA-1 and ICAM-1 co-localized at the Tck-FLS synapse, blocking the LFA-1/ICAM-1 interaction did not substantially inhibit Tck effector function. However, antibody blocking of membrane tumor necrosis factor (TNF)-alpha on the Tck surface did inhibit FLS cytokine production, thus illustrating a novel mechanism for involvement of TNF-alpha in cell-cell interactions in RA synovium and for the effectiveness of TNF-alpha blockade in the treatment of RA.

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

“…RA FLS become hyperplastic during disease and contribute to cytokine-mediated inflammatory joint destruction (Tran et al, 2007). To examine whether RA FLS respond to Takinib in a TNFα dependent manner, RA FLS were treated with titrations of Takinib in the presence of 0, 0.1, 10, and 30ng/ml TNFα for 24 and 48h and caspase 3/7 activity determined (Fig.…”

Evaluation of Anti-inflammatory Effects of Steroids and Arthritis-Related Biotherapies in an In Vitro Coculture Model with Immune Cells and Synoviocytes

“…These interactions contribute to the chronicity of inflammation, notably by increasing the pro-inflammatory cytokine production and the cell survival of synoviocytes (11–13). In our previous studies, the effects of cell interactions on pro-inflammatory cytokine production were studied using an in vitro model of coculture between mesenchymal cells and peripheral blood mononuclear cells (PBMC).…”

Synovial cellular and molecular markers in rheumatoid arthritis

“…T cells can also be activated by cocktails of pro-inflammatory cytokines (including cytokines present in RA synovium), and such T cells display an array of surface structures similar to T cells isolated directly from the RA joint[91]. Moreover, these cytokine-activated T cells (Tck) are especially potent in inducing macrophages to secrete TNF[92], and interact closely with FLS in vitro, which results in activation of both cell types[93, 94]. Surface structures involved in these interactions include membrane-anchored TNF on the Tck[93] and B7-H3 on the FLS[94].…”

“…Moreover, these cytokine-activated T cells (Tck) are especially potent in inducing macrophages to secrete TNF[92], and interact closely with FLS in vitro, which results in activation of both cell types[93, 94]. Surface structures involved in these interactions include membrane-anchored TNF on the Tck[93] and B7-H3 on the FLS[94]. FLS lack robust expression of CD80 (B7.1) and CD86 (B7.2), along with most other members of the B.7 family, but express B7-H3 constitutively, as do fibroblasts from other tissues[94].…”