Mitogens trigger a calcium-independent signal for proliferation in phorbol-ester-treated lymphocytes

Abstract

The activation of T lymphocytes by mitogens requires at least two signals; the first, delivered to T cells by a mitogen in conjunction with accessory cells (monocytes/macrophages), leads to the generation of the second signal, interleukin-2 (IL-2). The first signal also induces the expression of IL-2 receptors on the surface of a subpopulation of T cells; binding of IL-2 to its receptor then initiates a cascade of events culminating in DNA synthesis by these cells^1–4. Certain compounds act synergistically with mitogens in promoting T-cell proliferation by substituting for the activities of interacting cells or their products. For example, the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) has been shown to restore the ability of macrophage-depleted T-cell populations to respond to mitogenic lectins^5–7. Transmembrane fluxes of calcium, leading to increased free cytosolic calcium concentrations ([Ca²⁺]_i), have been demonstrated following mitogen binding to lymphocytes and have been implicated in the initiation of cell proliferation^8–10. We show here that the effect of TPA on lymphocyte proliferation occurs in the absence of extracellular Ca²⁺ or detectable changes in [Ca²⁺]_i, but only in the presence of mitogens. This suggests that in cells which have been incubated with the phorbol ester, mitogens can induce proliferation by a calcium-independent signal.