Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor‐α, but not interleukin‐10: Possible relevance to pathophysiology of rheumatoid arthritis

Previous studies in the laboratory have shown that the pro‐inflammatory cytokine tumor necrosis factor (TNF)‐α plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The mechanisms involved in regulating monocyte/macrophage cytokine production are not yet fully understood, but are thought to involve both soluble factors and cell/cell contact with other cell types. We and others have previously demonstrated that T cells activated through the T cell receptor/CD3 complex induce monocyte TNF‐α production by contact‐mediated signals. In this report, we investigated further whether T cells activated by cytokines in the absence of T cell receptor stimulation also regulate monocyte cytokine production. T cells were activated in an antigen‐independent manner using the cytokines interleukin (IL)‐15 or IL‐2 alone, or in combination with IL‐6 and TNF‐α. Subsequently, T cells were fixed and incubated with monocytes. Fixed, cytokine‐stimulated T cells induced monocytes to secrete TNF‐α in a dose‐dependent manner, but did not induce secretion of IL‐10, a potent endogenous down‐regulator of TNF‐α and other pro‐inflammatory cytokines. Stimulation of monocyte TNF‐α was markedly inhibited when T cells were physically separated from monocytes within the tissue culture well, confirming that T cell contact is necessary. T cell acquisition of monocyte‐activating capacity was shown to be dependent on the period of cytokine stimulation, with T cells activated for 8 days more effective than T cells activated for shorter periods. Addition of interferon‐γ or granulocyte/macrophage colony‐stimulating factor to the T cell/monocyte cultures enhanced T cell induction of monocyte TNF‐α by threefold and ninefold, respectively. The results from this model of cognate interaction suggest that cytokine‐stimulated T cells, interacting with macrophages in the rheumatoid synovial membrane, may contribute to the continuous excessive production of TNF‐α observed in the RA joint, and to the imbalance of pro‐inflammatory cytokines over anti‐inflammatory cytokines.