Dendritic cells (DCs) found in peripheral lymphoid tissue are very efficient stimulators of T cells, and thus cell-mediated immunity (CMI). However, it has recently been shown that efficient antigen presenting function of DCs is an acquired function manifest by mature DCs. The signals that induce the mature DC phenotype (high levels of MHC class II, co-stimulatory molecules such as B7.1, and B7.2, IL12 production etc.) are currently being resolved. One important component of DC maturating into fully competent Antigen Presenting Cells (APCs) appears to be the triggering of CD40 on the cell surface. Work in the Noelle lab has shown that loss of CD40 impairs CMI in several systems and eradicates the ability of mice to make protective immune responses to tumors. We propose that when CMI is impaired from loss of CD40 signaling, the lesion disrupts DC maturation and APC function, impairing the reciprocal stimulation of T cells. Preliminary studies show that signaling of DC via CD40 is a critical event in the development of CMI to tumors and I propose to study the basis for this dependence. 1. What fundamental changes in DC biology are induced by CD40 triggering, and what consequences do these changes have to T cell immunity? Although there are some data on the in vitro effects of CD40 on DCs, there are no studies that attempt to evaluate the in vivo role of CD40 on DC maturation and T cell immunity. My studies will investigate the in vivo impact of CD40 signaling on DC, CD4+ and CD8+ T cell cytokine production, expression of co-stimulatory molecules, migration and anatomical distribution. 2. How does DC CD40 signaling regulate systemic tumor immunity? I will assess the CD40 function of DCs in mediating the development of protective immune responses to tumor vaccines and whether CD154-transduced vaccines can be used as potent inducers of tumor immunity. 3. Is CD40 expression critical for the clonal expansion and differentiation of tumor specific CD4 and CD8 T cells. Using an HA-expressing tumor cell line, we will follow the induction of systemic immunity to tumor, and the HA-specific CD4+ and CD8+ responses with regard to establishment of memory and cytolytic activity.
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