TH1/TH2 CROSS-REGULATION

We present and analyze a model for the cross-regulation of the Th1 and Th2 helper cell subsets during an immune response by the regulatory cytokines interferon-gamma (IFN-gamma) and interleukin-10 (IL-10). IFN-gamma, secreted by Th1 cells, can inhibit the proliferation of Th2 cells. Interleukin-10, secreted by Th2 cells, inhibits cytokine production by Th1 cells. Based on these properties, the model shows that responses are expected to be dominated by either Th1 cells or Th2 cells but not both. Which type dominates is shown to depend principally on the relative efficiencies of activation of the responding Th1 and Th2 cells. However, our model, as well as numerous experiments, show that perturbations of the system, allow one to switch from a Th2 to a Th1 response, or vice versa. Our model can account for observed outcomes of parasitic infection and may also contribute to our understanding of immune responses to HIV infection as well as to tolerance to self components. It also predicts that in certain parameter ranges vaccination with low doses of live parasites can provide protection against subsequent encounters with high doses that normally induce disease. Experiments by Bretscher et al. (1992, Science 257, 539) on Leishmania major infection are consistent with this prediction. A similar strategy may also be relevant for the design of an AIDS vaccine. Lastly, our results indicate that Th1/Th2 cross-regulation is capable of generating a ''sneaking through'' phenomenon, and hence it may play a role in tumor immunity.