Gamma-delta T cells have unique features in comparison to alpha-beta T cells. It now has become clear that gamma-delta T cells recognize non-peptide and non-processed bacterial and environmental antigens, as well as stress-associated antigens expressed on epithelium and on primary carcinomas. Both in vitro and in vivo studies have demonstrated that Gamma-delta T cells can be differentiated into IFN-gamma (Th1-like)- and IL-4 (Th2-like)-producing cells. However, the molecular mechanisms underlying such differentiation have not been defined, and the precise role of the cytokines produced by gamma-delta T cells in vivo remains unknown. Our preliminary studies have demonstrated that gamma-delta T cells predominantly produce IFN-gamma upon activation, and the mechanisms that control gamma-delta T cell differentiation are different from CD4+ T cells. Furthermore, we have presented evidence that gamma-delta T cells play an important role in tumor immunity through their IFN-gamma production. Based on these data, we hypothesize that the molecular mechanisms for gamma-delta T cell differentiation, especially the factors that modulate gamma-delta T cell IFN-gamma secretion, are fundamentally different from those in alpha-beta CD4+ T cells. Moreover, we hypothesize that gamma-delta T cells play important roles in tumor immunity and in regulating the adaptive immune response (CD4+ and CD8+ T cell function) through their predominant production of IFN-gamma. To address these hypotheses, three specific aims are planned. First, delineation of the molecular mechanisms that control cytokine secretion by gamma-delta T cells. Here we will dissect the molecular mechanisms leading to IFN-gamma and IL-4 production by splenic gamma-delta T cells, focusing upon the different signaling pathways that have been well-studied in alpha-beta CD4+ T cells. Second, the role of gamma-delta T cells in tumor immunity in vivo through IFN-gamma production will be investigated. Here, we will use reconstituted mice in which T cell composition is intact except the ability of gamma-delta T cells to produce IFN-gamma allowing us to define the role of IFN-gamma produced by gamma-delta T cells in protective tumor response and the mechanisms. Finally, we will determine the roles of gamma-delta T cells in regulating the adaptive immune response using ovalbumin protein or peptide immunization system, to define the role of gamma-delta T cells in the development of antigen-specific CD4+ and CD8+ T cell effector function.
