In response to antigen stimulation, naive CD4+ T cells differentiate into effector T helper (Th)l or Th2. Thl cells produce IFNgamma and TNFbeta, which are required for cell-mediated inflammatory reactions, and Th2 cells secrete IL-4, IL-5, IL-10 and IL-13, which mediate B cell activation and differentiation. The decision of naive CD4 + T cells to become Thl and Th2 has important consequences in the progression of diseases. Cytokine represent one of the principal factors that determine the Thl and Th2 differentiation. IL-4 causes differentiation into Th2 cells, whereas IL- 12, IL- 18 and IFNgamma drive differentiation into Th 1 cells. Our studies demonstrate that IL-6 initiates the production of IL-4 by CD4+ T cells and further differentiation into effector Th2, but IL-6 also inhibits Th I differentiation by interfering with IFNgamma production and signaling in CD4+ T cells. Two independent molecular mechanisms are used by IL-6 to control CD4+ Thl and Th2 differentiation. Activation of NFAT and IL4 gene expression is responsible for IL-6-mediated Th2 differentiation, while upregulation of the suppressor of cytokine signal (SOCS)l expression and inhibition of IFNgamma signaling are the molecular mechanisms that mediate inhibition of Thl differentiation by IL-6. A predominant Th2 immune response has been observed in some lung diseases (e.g. asthma, allergy) and development of this type of response has been associated with the progression of disease. We believe that cytokines secreted by the lung environment (e.g. epithelial) cells, smooth muscle cells) largely contribute to the development of these predominant Th2 responses. Specifically, we propose that production of IL-6 by airway epithelial cells promotes the generation of effector CD4+ Th2 cells by inducing NFA T-mediated IL-4 gene expression, and inhibits the generation of effector CD4+ Thl cells by interfering with IFNgamma signaling. To address this hypothesis we will determine whether: 1) production of IL-6 by lung epithelial cells induces IL-4 and inhibits IFNgamma production by CD4+T cells in vitro. by examining the production of these cytokines in CD4+ T cells activated in the presence of lung epithelial cells from wild type and IL-6 deficient mice, and from control and asthmatic patients; 2) production of IL-6 by lung epithelial cells induces IL-4 and inhibits IFNgamma production by CD4+T cells in vivo, by examining CD4+ T cells in mice that express IL-6 exclusively in lung epithelial cells and in mice that are unable to express IL-6 exclusively in lung epithelial cells; 3) inhibition of NFAT in T cells prevents the generation of lung effector Th2 CD4+ T cells and the development of asthma.