T helper (Th) lymphocytes can be divided into two subsets on the basis of their pattern of cytokine secretion. The Th1 cells secrete mainly interleukin-2 (IL-2), interferon gamma (IFN-gamma) and lymphotoxin. Th2 cells secrete mainly IL-4, IL-5, IL-6 and IL-10. T helper derived cytokines regulate the activity of many cells of the immune system, and determine whether the immune response will be dominated by antibody production or whether it will be a cell-mediated response. This can have important clinical consequences as certain diseases have been shown to be dominated by one response or the other. Th1- and Th2-type cytokines exert both positive and negative influences on the T cells themselves. IFN-gamma has an inhibitory, indirect effect on the proliferation of Th2 cells, but no inhibitory effect on Thl cells. This inhibitory effect is mediated by the action IFN-gamma on the costimulatory cytokine IL-1. The costimulatory cytokine IL-12 is able to induce proliferation in response to IL-4 in Th1 cells but not in Th2 cells. The different/opposing effects cytokines induce in Th1 and in Th2 lymphocytes may be due to the usage of different signaling pathways in response to these molecules. In addition, cytokines produced by one subset may alter the cytokine signaling transduction in the other T cell subset. These hypotheses are likely to explain the available experimental data. The work proposed here will focus on the elucidation of the signal transduction pathways stimulated by cytokines in Thl and Th2 cells and on how these pathways are modified by the presence of other regulatory cytokines. The results anticipated from this work are to provide important new information concerning the control of activation and growth of these two important Th cell subsets and also to better describe how cytokines may interact together on the same cell.
