Accessory factors involved in murine T cell activation. Distinct roles of interleukin 6, interleukin 1 and tumor necrosis factor

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Abstract
Interleukin (IL) 6 was compared to other macrophage-derived products for its capacity to support the proliferation of accessory cell-depleted T cells. Monoclonal anti-IL 6 antibodies were found to inhibit completely the “accessory activity” of macrophage supernatants, thus demonstrating the central role played by IL 6 in T cell activation. IL 6 was apparently more critical for initiating than in maintaining T cell proliferation because anti-IL 6 antibodies lost all inhibitory activity when added late to the culture. Moreover, IL 6 was not the only accessory factor required for optimal T cell proliferation. Using low-density cultures to minimize the number of contaminating accessory cells, we found that significant proliferation of CD4 cells was obtained only in the presence of both IL 6 and IL 1. In contrast, with CD8 cells substantial proliferation was obtained with IL 6 alone. This response could, however, be enhanced by IL 1. Tumor necrosis factor (TNF) and granulocyte/macrophage colony-stimulating factor showed no activity in these assays. The concentrations of IL 1 and of IL 6 required to support optimal proliferation were 10 pg/ml and 1 ng/ml, respectively. Analysis of the mechanisms underlying T cell activation by IL 1 and IL 6 indicated that both cytokines were required for optimal production of IL 2 but that IL 6 alone was sufficient to confer IL 2 responsiveness. For CD8 cells, this effect was observed with doses of IL 6 about 100 times lower than those required for the induction of IL 2 secretion (0.001 vs. 0.1 ng/ml). TNF, which was not capable of inducing IL 2 secretion, was also found to induce IL2 responsiveness but only at a concentration ≈ 1000 times higher than that of IL 6. In accordance with these observations, IL 6 and to a lesser extent TNF were found to enhance IL 2R expression by CD8 cells. Interestingly, this enhancing effect was totally dependent on the presence of IL 2.