Critical impact of the kinetics of dendritic cells activation on the in vivo induction of tumor-specific T lymphocytes.
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 (Th(1)) responses, whereas at later time points, the same cells preferentially prime Th(2) cells [Langenkemp, A. et al., Nat. Immunol. 1: 311-316, 2000]. Because the immune response against cancer strongly depends on CTLs of Th(1)-like phenotype (Tc(1)), 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 Tc(1) 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 Tc(1) 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.
Camporeale
Annalisa
A
Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico H San Raffaele, 20132 Milan, Italy.
Boni
Andrea
A
Iezzi
Giandomenica
G
Degl'Innocenti
Elena
E
Grioni
Matteo
M
Mondino
Anna
A
Bellone
Matteo
M
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D007114:Immunization; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D018664:Interleukin-12