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Critical Impact of the Kinetics of Dendritic Cells Activation on the in Vivo Induction of Tumor-specific T Lymphocytes¹

Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico H San Raffaele, 20132 Milan, Italy

Dendritic cells (DCs) need activation for the priming of antigen-specific immune responses. Recently activated DCs were described to prime in vitro strong T helper cell type 1 (Th₁) responses, whereas at later time points, the same cells preferentially prime Th₂ cells [Langenkemp, A. et al., Nat. Immunol. 1: 311–316, 2000]. Because the immune response against cancer strongly depends on CTLs of Th₁-like phenotype (Tc₁), we verified here whether the kinetics of DCs activation also impacted on in vivo priming of tumor-specific CTLs. After pulsing with the CTL epitope TRP-2_180–188, bone-marrow-derived DCs, exposed to lipopolysaccharide (LPS) for 8 h (8hDC), elicited a more powerful Tc₁ response in C57BL/6 mice than did untreated DCs, or DCs exposed to LPS for 48 h (48hDC). Indeed, 8hDCs were the most potent protective and therapeutic vaccine against B16 melanoma. Despite a higher expression of MHC and costimulatory molecules by 48hDCs, 8hDCs and 48hDCs showed comparable allostimulatory and migration potential, and susceptibility to CTL-mediated apoptosis. However, 8hDCs exhibited a significantly higher interleukin (IL)-12 production potential. Release of IL-12 was necessary to induce potent Tc₁ cells, because DCs from IL-12p40^-/- mice, irrespective of their maturation level, generated low CTL responses, comparable with 48hDCs and 0hDCs from wild-type animals. Our data are relevant for the design of DC-based vaccines.

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