We have examined the mechanisms underlying the activation of human T cells by IL-1 and IL-6. We report that PHA-stimulated accessory cell-depleted tonsillar T cells fractionated on the basis of their density show a high degree of heterogeneity in their proliferative response to these cytokines, inasmuch as small dense lymphocytes essentially fail to respond whereas large cells proliferate extensively. This differential response could be ascribed to the fact that only the large cells produced IL-2 under these circumstances, thus providing unequivocal evidence for the existence of an IL-2-mediated step in the activation of human T cells by IL-1 and IL-6. The synergy between IL-1 and IL-6 was found to result from their complementary effects on the production of and response to IL-2, with IL-1 playing a preponderant role in the induction of IL-2, and IL-6 being required, in addition to IL-1, for optimal IL-2-responsiveness. Using small tonsillar T cells, it was possible to show that, concomitant with the enhanced response to IL-2, IL-6 induced a marked increase in cell size and in protein synthesis. In the absence of other factors, this activation was not followed by entry into S phase, suggesting that the essential role of IL-6 in T cell activation is to induce the cells to move from G0 to G1, where they become more responsive to the small amounts of IL-2 induced by IL-1.