Dendritic cells : tools to induce efficient T cell mediated immunity

Immune responsiveness is carefully regulated. Cells of the immune system have to respond adequately to invading micro-organisms and possibly to transformed cells, but tolerance for the own body constituents needs to be preserved. Dendritic cells (DC) comprise a family of professional antigen presenting cells (APC) that play a central role in the regulation of the immune response. Immature DC, located in the periphery, can efficiently take up Ag, but lack the co-stimulatory signals for effective T-cell activation. Upon maturation, DC migrate to secondary lymphoid organs and increase the expression of co-stimulatory molecules and MHC molecules. Mature DC are very efficient in priming na____ve T-cells. In contrast to their T-cell priming capacity, DC in peripheral tissues constitutively process and present Ag in the absence of pathogen-related or endogenous inflammatory stimuli, and make a major contribution to peripheral tolerance by inducing unresponsiveness or deletion of specific T-cells. The central role of DC in controlling immunity makes these cells attractive tools for many clinical situations that involve T-cells: induction of tolerance in case of transplantation, allergy and autoimmune disease and induction of efficient T-cell responsiveness in case of infection and tumors. Many tumor components do not elicit Ag-specific T-cell responses in patients, which may be due to the absence of functional DC in tumors or the secretion of factors by tumor cells that reduce DC development and function. Application of tumor Ag to DC ex vivo and reinfusion of these DC leads to induction of specific immunity. In animals this strategy can lead to protection against tumors and even a reduction in size of established tumors. At present similar studies are carried out in patients. The research described in this thesis focuses on the requirements for induction of efficient cytotoxic T lymphocyte (CTL)- responses and tumor immunity by DC. Different modes of Ag presentation were studied for the induction of CTL-responses and tumor protection.