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Induction of antigen-specific CD8 T cells by monocyte-derived dendritic cells Influence of DC maturation on the recruited T cell repertoire



Induction of antigen-specific CD8 T cells by monocyte-derived dendritic cells Influence of DC maturation on the recruited T cell repertoire



Blood 98(11 Part 1): 510a, November 16



Dendritic cells (DC) are essential for the generation of primary adaptive immunity, and it is recognized that their modulation of T cell responses depends greatly on their stage of maturation and pattern of cytokines secreted. We used an in vitro model to assess the ability of immature and mature DC to induce antigen-specific CD8 T cells and compared the repertoire of the recruited T cells. Monocyte-derived DC differentiated with GM-CSF and IL-13 (Dendritophages(R), Dphi) were maturated with either the synthetic double-stranded RNA polyI:C+ anti-CD40 mAb, or with a bacterial extract (Ribomunyl), in presence or absence of IFNgamma. Addition of IFNgamma at the onset of maturation allowed higher secretion of IL-12 concomitant with lower secretion of IL-10. Kinetics studies showed that a contact as short as 3 h with maturation agents triggered an activation process that then proceeded and completed spontaneously. Most of IL-12 secretion occurred between 6 and 20 h from the initiation of maturation. Therefore, we analysed the function of Dphi that had been in contact with maturation agents for 3, 6, or 20 h. After maturation, Dphi were pulsed with a MelanA/MART1-derived peptide (26-35/27L) and used to stimulate autologous purified CD8 T cells. Using cytotoxicity assays, IFNgamma-ELISPOT, proliferation assays and tetramer staining, we found that only mature Dphi were able to generate and sustain antigen-specific CD8 T cells in absence of CD4 cells and exogenous cytokines. However, MelanA/MART1-specific CD8 cells could be induced by immature Dphi if exogenous cytokines (IL-12 and IL-6, IL-2 and IL-7) were added during stimulation. When Dphi maturation was triggered before the in vitro stimulation, a 6-h incubation in presence of Ribomunyl/INFgamma was optimal for the generation of CD8 responses, and mature Dphi were 80 to 400 times more potent than immature Dphi. Finally, the repertoire of the MelanA/MART1-specific T cells obtained was characterised by Immunoscope analysis. We found that, despite their dissimilar frequency, the CD8 generated were qualitatively similar. In the same individual, the MelanA/MART1-specific repertoires expanded by Dphi maturated by different agents were partially overlapping although in all cases very diverse. Overall, our results indicate that Dphi matured with Ribomunyl+IFNgamma are strong inducers of CD8 T cell responses and therefore constitute a useful tool for the development of future therapies against cancer.

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Accession: 035125215

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