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In current clinical trails, whole yeast-based immunotherapy expressing hepatitis C viral antigens demonstrated statistically significant improvement in end of treatment responses when combined with type I interferon based standard of care, even in standard of care resistant patients. Although preclinical data suggest yeast vaccination, such as type I interferon, facilitates CD8 T-cell immunity, the capacity of yeast to generate immunity in patients resistant to type I interferon calls into question the mechanism(s) underpinning the efficacy of this approach. We show yeast and a Toll-like receptor exclusive agonist, Pam3Cys, differ in CD8 T-cell generation when combined with an agonistic CD40 antibody. Although both yeast and PamCys were largely Toll-like receptor dependent, the primary CD8 response generated by yeast was significantly less than Pam3Cys in wild-type hosts even in a CD4 T-cell-deficient setting. In addition, immunization of IL6−/− mice with yeast produced a 3-fold to 6-fold increased CD8 response while the Pam3Cys response was unaffected. The yeast but not Pam3Cys-driven CD8 response was inhibited in both wild-type and IL-6−/− hosts by blocking interleukin (IL)-12. In addition, IL6−/− mice had increased CD86 expression on their dendritic cells after yeast immunization also inhibited by IL-12 blockade. Collectively, our results indicate the CD8 T-cell response to yeast but not Pam3Cys is influenced by IL-6-mediated control of IL-12 critical for dendritic cell activation. To our knowledge this is the first demonstration that yeast directly influence IL-12-associated CD8 T-cell immunity providing an additional route whereby recombinant yeast may provide efficacy independent of type I interferon.