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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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Submitted November 7, 2007
Accepted December 6, 2007
Targeting dendritic cell signalling to regulate the response to immunisation
David Escors, Luciene Lopes, Rongtuan Lin, John Hiscott, Shizuo Akira, Roger J. Davis, and Mary K. Collins*
Infection and Immunity, University College London, London, United Kingdom
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada
Department of Host Defence, Rsearch Institute for Microbial Diseases, Osaka University, Osaka, Japan
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
* Corresponding author; email: mary.collins{at}ucl.ac.uk.
Dendritic cells (DC) 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 DC, substantially enhanced the anti-tumor immune response and prolonged survival of tumor-bearing mice. Activation of ERK increased TGF- expression while expression of a constitutively activated interferon regulatory factor-3 (IRF3) stimulated IL-10 secretion by DC. 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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