In order to determine the factors underlying the impaired natural cytotoxic (NC) activity in multiple sclerosis (MS) patients, we have analysed the interleukin 2 (IL-2)-interferon gamma-(IFN gamma)-NC activity regulatory circuit in 40 MS patients and 40 matched healthy controls. Exogenous recombinant IFN gamma (rIFN gamma) enhanced NC activity in peripheral blood lymphocytes (PBL) derived from MS patients and controls equally well. In contrast, PBL from MS patients showed a significantly lower increase of NC activity in response to IL-2 than healthy controls. This defect in responsiveness was independent of the dose of IL-2. Even at the highest dose of rIL-2 (1000 U/ml), MS patients showed a decreased response. PBL from MS patients required a 2 to 10 times higher dose of IL-2 to reach NC activity levels comparable to controls. In healthy individuals IL-2 can act upon both Fc gamma R+ and Fc gamma R- NC precursor cells. The decreased responsiveness to IL-2 is not confined to one subpopulation of IL-2-responsive precursor cells because depletion of Fc gamma R+ cells before culture in the presence of IL-2 revealed no significant differences in the contribution of Fc gamma R+ precursor cells to the IL-2 enhanced NC activity between MS patients and controls. Also the number of IL-2-responsive precursor cells appeared to be normal since the number of Fc gamma R+ cells in MS patients and controls was comparable. PBL from MS patients produced significantly lower amounts of IFN gamma upon stimulation with IL-2. Analysis of the different parameters of the regulatory circuit at the population level showed, both for patients and controls, a significant correlation between IFN gamma production and increase of NC activity induced by IL-2. Also the endogenous NC activity and IFN gamma production, both in patients and controls, were correlated. At the individual level, defects in NC activity could not be linked to another parameter of the regulatory circuit.