Cognate Dependent Interactions

The Importance of the T Cell

The synovium in rheumatoid arthritis (RA) is very cellular, with several different cell types including macrophages and T cells, in close proximity [6]. This biological appearance suggests that contact signals between macrophages and T cells could be of importance in vivo in modulating macrophage function. Our prior studies have found that TNFa production in RA synovium is T cell-dependent, as removal of CD3-positive T cells from RA synovial mononuclear cells resulted in significant reduced macrophage TNFa production [7].

Direct contact-mediated interactions have been studied by several groups, initially J.-M. Dayer's, using transformed T cell and monocytic lines, and were found to play an important role in inducing the synthesis of several cytokines including IL-1 p, TNFa, IL-10 as well as destructive metalloproteinases [8-12]. We have studied T cell-monocyte cognate interactions using cells isolated from the peripheral blood of normal donors and also using synovial T cells. A key observation was that the manner in which T cells were activated influenced the profile of cytokines induced in the monocytes. Thus if blood T cells were activated with cross-linked anti-CD3 (a mimic of antigen stimulation) this induced the production of both pro-inflammatory TNFa and anti-inflammatory IL-10 in monocytes [12]. However, if the T cells were stimulated with a cocktail of cytokines (TNFa, IL-2 and IL-6) for 8 days, a model of bystander activation, TNFa but not IL-10 production ensued [11]. This suggested to us that cytokine-stimulated T cells (Tck) may physiologically resemble a highly pro-inflammatory situation, and T cells in RA synovial tissue induce macrophage TNFa production because they could induce an unbalanced pro-inflammatory cytokine response from monocytes, and thus could be part of a vicious cycle (Fig. 1). The corresponding T cell phenotype would appear to be of importance, as a study by Dayer's group [13] sug-

Bystander activation - "vicious cycle"

Fig. 1 Cytokine disequilibrium induced by Tck. Peripheral blood T cells activated with cross-linked anti-CD3 (Ttcr) for 48 h results in contact-induced production of TNFa and IL-10 in monocytes. T cells stimulated with a cocktail of cytokines (TNFa, IL-2 and IL-6) for 8 days (by-stander activation) termed Tck cells results in TNFa but not IL-10 production

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