Requirement of mature dendritic cells for efficient activation of influenza A-specific memory CD8(+) T cells

It is critical to identify the developmental stage of dendritic cells (DCs) that is most efficient at inducing CD8(+) T cell responses. Immature DCs c an be generated from monocytes with GM-CSF and IL-4, while maturation is ac complished by the addition of stimuli such as monocyte-conditioned medium, CD40 ligand, and LPS, We evaluated the ability of human monocytes and immat ure and mature DCs to induce CD8(+) effector responses to influenza virus A gs from resting memory cells, We studied replicating virus, nonreplicating virus, and the HLA-A*0201-restricted influenza matrix protein peptide. Sens itive and quantitative assays were used to measure influenza A-specific imm une responses, including MHC class I tetramer binding assays, enzyme-linked immunospot assays for IFN-gamma production, and generation of cytotoxic T cells. Mature DCs were demonstrated to be superior to immature DC in elicit ing IFN-gamma production from CD8(+) effector cells. Furthermore, only matu re DCs, not immature DCs, could expand and differentiate CTL precursors int o cytotoxic effector cells over 7 days. An exception to this was immature D Cs infected with live influenza virus, because of the virus's known maturat ion effect. Finally, mature DCs pulsed with matrix peptide induced CTLs fro m highly purified CD8(+) T cells without requiring CD4(+) T cell help. Thes e differences between DC stages were independent of Ag concentrations or th e number of immature DCs, In contrast to DCs, monocytes were markedly infer ior or completely ineffective stimulators of T cell immunity, Our data with several qualitatively different assays of the memory CD8(+) T cell respons e suggest that mature cells should be considered as immunotherapeutic adjuv ants for Ag delivery.