TNF and infection: We considered several possibilities to account for the inductive effects of heat-inactivated vaccinia: (i) heat-treatment liberates an inducing factor from the virion that triggers IFN-α and TNF production, whether or not the heated particles are taken up by the pDCs; (ii) heat-inactivated viral particles are taken up by pDCs and generate inducing substances intracellularly that are not normally present during vaccinia infection; or (iii) Heat-VAC infection produces inducer(s) present during normal infection with vaccinia, but fail to generate inhibitor(s) of innate immune signaling in pDCs.