Cellular immunity is key to our resistance against cancer and chronic infections. Effective cell-mediated immunity requires the participation of dendritic cells (DC), CDS+ T cells (CTL), and CD4+ IFN-gamma- producing type-1 T helper (Thl) cells. CD40L-expressing CD4+ cells are a source of DC-mediated helper signals for the optimal induction and persistence of cytotoxic CD8+ T cell responses. In contrast, it is unclear whether and to what extent the optimal magnitude and the Thl polarization of CD4+ cell responses depend on the feedback signals from CD8+ T cells. Based on our recent observations that human CD8+ T cells activate DC and prime them for high IL-12 production, we hypothesize that at least some populations of CD8+ T cells may provide DC-mediated helper signals for tumor-specific Thl cells and may be utilized to boost the effectiveness of DC -mediated cancer immunotherapy. Defining the role(s) of CD8+ T cells in the development and proper functioning of Thl cells is important for our understanding of the pathology and for the design of immunotherapy in cancer and chronic infections with intracellular pathogens. It may also provide tools to correct the aberrant Th1/Th2 response patterns in autoimmune diseases and allergy. This study will pursue three specific aims: 1. We will analyze the impact of different populations of CD8+ T cells on the ability of DC to provide activating, polarizing, and survival signals for naive and memory CD4+ Th cells. 2. Determine the DCl-polarizing potential of virus-specific and tumor-specific CD8 T cells, and evaluate in vitro the potential for using """"""""heterologous CD8 help"""""""" from virus-specific CD8 T cells to boost the induction of human tumor-specific Thl responses. 3. Determine the roles of virus-specific and tumor-specific CD8+ T cells in the development of Thl-type immunity in vivo, and to use the """"""""heterologous"""""""" CD8 help to boost the induction anti-tumor immunity by DC-mediated vaccination.
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