cloned CD4 ÷ T-cell population which is activated by foreign pep- tide presented by whole spleen cells is paralyzed by the same antigen when presented by irradiated resting B cells 3 or by the T-cell clone 4 itself. When viewed objectively (which I grant is impossible!), the exist- ence of natural autoantibodies, spontaneous autoimmunity, and the ability to induce tolerance to foreign proteins should stand out as striking anomalies in a paradigm of self/nonself discrimination. There are three possible responses to such distressing observations. The first is to deny that the anomaly exists, for instance to say that it is the immune system and not the mind of the immunologist which decides what is self and what is nonself. The sec- ond is to claim that the immune system is not perfect or to com- plicate models that were once sim- ple and beautiful. The third is to acknowledge crisis and change the paradigm rather than ruin the model. In the quest for a new para- digm of immune function, we need only to refer back to Darwin's theo- ry of evolution by natural selection. As lrun Cohen has stated s, the immune system has evolved not to discriminate self from nonself but to enhance fitness. How could a self/nonself discrimination kaleidoscope be evolutionarily disadvantageous? Because an organism with a perfect S/NS discrimination would reject exogenous genetic elements that might benefit the host. Thus, a bet- ter solution is for the immune sys- tem to react only after a foreign microbe has damaged tissue. Lymphocytes do this by employing professional APCs (for example dendritic cells) as sentinels of tissue destruction. If only professional APCs can turn on virgin T cells and professional APCs induce tolerance to their antigens in the thymus 6, then unresponsiveness of virgin T cells to all self antigens is ensured. The model predicts, then, that non- professional APCs cannot deliver a costimulatory signal (signal 2) to virgin T cells. This appears to be true for B cells as APCs, which have been found 7'8 to induce tolerance in virgin T cells specific for foreign antigens (a clear anomaly in a S/NS discrimipaticn paradigm!). If indeed the immune system does not discriminate self from nonseif, then Langman and Cohn's modification 9 of the original two signal model is unnecessary. If, however, my theory is incorrect, I would readily concede that the Bretscher-Cohn-Langman formu- lation is the only model ever pro- posed which provides a complete letters and consistent mechanism of S/NS discrimination. In any case. i hope that such disputes over details ghoaid not detract from the fact that the two signal model has proven a valuable guide to experimenters and is, in my opinion, the most important contribution to immu- nology since the clonal selection theory of acquired immunity. Ephraim Fuchs 1518 Park Avenue, #203N Baltimore, MD 21217, USA. References 1 Bretscher, P.A. and Cohn, M. (1970) Science 161, 1041-1049 2 Lafferty, K.J. and Cunningham, A.J. (1975) Aust. J. Exp. Biol. Med. Sci 53, 27-42 3 Ashwell,J.D., Jenkins, M.K. and Schwartz, R.H. (1% 8) J. lmmunol. 141, 2536-2544 4 Lamb, J.R., Skidmore, B.J. et al. (1983) J. Exp. Med. 157, '-434-1447 5 Cohen, !.R. (1992) lmmunol. Today 13,441-444 6 Matzinger, P. and Guerder, S. (1989) Nature 338, 74-76 7 Eynon, E.E. and Parker, D.C. (1992) J. Exp. Med. 175, 131-138 8 Fuchs, E.J. and Matzinger, P. (1992) Science I 156-1 !59 9 Langman, R.E. (1989) The Immune System, Academic Press Producer cells of interleukin-12 A recent review by F.E.G. Cox and F.Y. Liew (Immunol. Today (1992) 13, 445-448) describing the role of different cytokines in parasitic infection attributed the production ot IL-12 to T helper TH1 cells. We believe there is no evidence for the production of NKSF/IL-12 by this cell type at the present time. Although several studies have been published since tile original identification of IL-12 by our group I, a characterization of the natural producer cells has been described only recently-'. Production of biologically active IL-12, formerly called natural killer cell stimulatory factor (NKSF) or cytotoxic lymphocyte maturation factor (CLMF), was originally described in three Epstein-Barr virus (EBV)-transformed cell lines, RPMI-8866, NC37, and ADP ~--~. The purified IL-!2 appears in SDS- PAGE as a 70 kD heterodimer protein, that resolves in reduced conditions to two chains of 35 and 40 kD. Recently we have shown that treatment with bacterial products such a~ fixed staphylococ- cus aureus Cowan 1 strain (SAC) or LPS induces IL-12 production by resting peripheral blood mono- nuclear cellsL Our data suggest that IL-12 is produced by cell types with accessory or antigen-present- ing ability, including monocytes, B cells and possibly other minor accessory cell populations. T and NK cells, on which the biological activity of IL-12 and the presence of IL-12 receptor have been unequivocally demonstrated 4"~, do not appear to be capable of pro- ducing IL-122. Like many other cell types, hematopoietic or not, T and NK cells express p35 mRNA, but not p40 mRNA, the expression of which is highly regulated and present only in cell types able to produce biologically active IL-12 heterodimer ~. IL-12, produced by accessory cells in response to bacterial infec- tion, plays at least two major roles in the response: (a) it induces and is probably necessary for efficient production of IFN-y by NK and T cells and therefore regulates phagocyte activation by IFN-y in inflammationl; (b) it induces the differentiation of TH1 cell clones while inhibiting the differentiation of IL-4-producing T cells6. IL-12 is therefore likely to participate in the Immunology Today 237 Vol. 14 No. 5 1993