IMMUNOBIOLOGY Targeting dendritic cell signaling to regulate the response to immunization

Dendritic cells (DCs) are key regulators of the immune system; they capture anti-gens and then can either stimulate an immune response or induce tolerance. Our aim was to activate individual DC signaling pathways to regulate the im-mune response. We therefore expressed constitutive activators of mitogen-activated protein kinase (MAPK) path-ways or the interferon pathway, together with tumor antigens, using lentivectors. Triggering of p38 activated DCs substan-tially enhanced the antitumor immune response and prolonged survival of tumor-bearing mice. Activation of extra-cellular signal–regulated kinase (ERK) increased TGF- expression while expres-sion of a constitutively activated inter-feron regulatory factor-3 (IRF3) stimu-lated 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 vec-tor or DC immunization; vaccine re-sponses to foreign or tumor antigens can be enhanced and harmful responses to self-antigens or introduced transgenes can be reduced. (Blood. 2008;111