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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3050-3061.
Prepublished online as a Blood First Edition Paper on January 7, 2008; DOI 10.1182/blood-2007-11-122408.
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IMMUNOBIOLOGY
Targeting dendritic cell signaling to regulate the response to immunization
David Escors1,
Luciene Lopes1,
Rongtuan Lin2,
John Hiscott2,
Shizuo Akira3,
Roger J. Davis4, and
Mary K. Collins1
1 Infection and Immunity, University College London, London, United Kingdom;
2 Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC;
3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and
4 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester
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-β 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.
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