Cyclosporin inhibits a two-signal mechanism for the generation of cytotoxic NK-like cells, from small lymphocyte precursors.

Cytotoxic cells resembling NK cells are generated from CD 3- small, lymphokine (LK) nonresponsive precursor cells during an 8 day culture period with mitomycin C-treated autologous T cell blasts and LK. Recombinant interleukin 2 (rIL2) can replace LK in this coculture system. Both stimuli are required for the generation of the cytotoxic cells, which can then be maintained in short term cultures by LK alone. The generation of the cytotoxic cells was inhibited in cultures containing 0.1 micrograms/ml cyclosporin (Cys). Cys did not inhibit the LK dependent growth of the cytotoxic cells. Cys also inhibited the mitogen and LK dependent stimulation of purified T cells, but did not inhibit the LK dependent proliferation of T cell blasts. In contrast to the results for the generation of the cytotoxic cells, Cys did not inhibit the activation/growth of peripheral blood NK cells by LK or rIL2. These studies support the notion that the precursors of the NK-like cytotoxic cells are at an earlier stage of differentiation than peripheral blood NK cells responsive to LK alone, and that the precursor cells are triggered into a differentiation pathway leading to the NK-like cytotoxic cells by a two-signal mechanism.