Targeting dendritic cell signaling to regulate the response to immunization.
Dendritic cells (DCs) are key regulators of the immune system; they capture antigens and then can either stimulate an immune response or induce tolerance. Our aim was to activate individual DC signaling pathways to regulate the immune response. We therefore expressed constitutive activators of mitogen-activated protein kinase (MAPK) pathways or the interferon pathway, together with tumor antigens, using lentivectors. Triggering of p38 activated DCs substantially enhanced the antitumor immune response and prolonged survival of tumor-bearing mice. Activation of extracellular signal-regulated kinase (ERK) increased TGF-beta expression while expression of a constitutively activated interferon regulatory factor-3 (IRF3) stimulated IL-10 secretion by DCs. ERK and IRF3 suppressed the immune response and stimulated expansion of regulatory T cells. These results provide a toolkit to regulate immune responses to viral vector or DC immunization; vaccine responses to foreign or tumor antigens can be enhanced and harmful responses to self-antigens or introduced transgenes can be reduced.
Escors
David
D
Infection and Immunity, University College London, London, United Kingdom.
Lopes
Luciene
L
Lin
Rongtuan
R
Hiscott
John
J
Akira
Shizuo
S
Davis
Roger J
RJ
Collins
Mary K
MK
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007114:Immunization; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation
D016207:Cytokines; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020928:Mitogen-Activated Protein Kinases