Accessory Factors Involved in Murine T Cell Activation. Distinct Roles of Interleukin 6, Interleukin 1 and Tumor Necrosis Factor

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-IL6 antibodies were found to inhibit completely the "accessory activity" of macrophage supernatants, thus demonstrating the central role played by IL6 in T cell activation. IL6 was apparently more critical for initiating than in maintaining T cell proliferation because anti-IL6 antibodies lost all inhibitory activity when added late to the culture. Moreover, IL6 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 IL6 and IL1. In contrast, with CD8 cells substantial proliferation was obtained with IL6 alone. This response could, however, be enhanced by IL1. Tumor necrosis factor (TNF) and granulocyte/macrophage colony-stimulating factor showed no activity in these assays. The concentrations of IL1 and of IL6 required to support optimal proliferation were 10 pg/ml and 1 ng/ml, respectively. Analysis of the mechanisms underlying T cell activation by IL1 and IL6 indicated that both cytokines were required for optimal production of IL2 but that IL6 alone was sufficient to confer IL2 responsiveness. For CD8 cells, this effect was observed with doses of IL6 about 100 times lower than those required for the induction of IL2 secretion (0.001 vs. 0.1 ng/ml). TNF, which was not capable of inducing IL2 secretion, was also found to induce IL2 responsiveness but only at a concentration approximately equal to 1000 times higher than that of IL6. In accordance with these observations, IL6 and to a lesser extent TNF were found to enhance IL2R expression by CD8 cells. Interestingly, this enhancing effect was totally dependent on the presence of IL2.