Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity.
Elimination of malignant cells and intracellular infections involves collaboration between CTLs and Th1 inflammation. Dendritic cells drive this response via costimulation and cytokines. We have defined key signals required for the exponential expansion of specific CD8(+) T cells in vivo in mice. Immunization with two or more TLR agonists, anti-CD40, IFN-gamma, and surfactant were sufficient to drive unprecedented levels of CD8 response to peptide or protein Ag and highly polarized Th1 CD4 responses. CD40 signaling was required for CD8 expansion but could be provided by a concomitant CD4 Th response in place of anti-CD40. Triggering of these pathways activated migration and activation of myeloid and plasmacytoid dendritic cells and secretion of IL-12. Cross-presentation can thus be exploited to induce potent cytotoxic responses and long-term memory to peptide/protein Ags. When combined with a tumor-associated peptide from tyrosinase-related protein 2, our combined adjuvant approach effectively halted tumor growth in an in vivo melanoma model and was more effective than anti-CD40 and a single TLR agonist. Antitumor immunity was associated with long-lived effector memory CD8 cells specific for the naturally processed and presented tumor Ag, and tumor protection was partially but not entirely dependent on CD8 T cells. This flexible strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development.
Wells
James W
JW
Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, United Kingdom.
Cowled
Christopher J
CJ
Farzaneh
Farzin
F
Noble
Alistair
A
D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000627:therapeutic use; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D049109:Cell Proliferation; D045142:Cross-Priming; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology*; D004357:Drug Synergism; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D011971:Receptors, Immunologic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists
D000906:Antibodies; D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D019496:Cancer Vaccines; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase