The role of interleukin-12 for mTOR regulation of memory CTLs

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A major goal of vaccines is to induce functional immune memory, and efforts to improve the efficacy of vaccines targeting memory CTLs have revealed an important immunoregulatory role of rapamycin, a specific mTOR inhibitor. While inflammatory cytokines are critical for memory CTLs formation, it is unknown if cytokines such as IL-12 mediate rapamycin's regulation during infection. Inhibition of mTOR by rapamycin represses CTL expansion but enhances central memory during vaccinia virus infection in mice. Without IL-12, immunoregulatory effects of rapamycin on CTL expansion and subsequent memory formation are diminished, yet present compared to CTLs not treated with rapamycin. In infected mice, rapamycin directly enhances IL-12 signaling in WT CTLs by upregulating IL-12 receptor-B2 and STAT4 phosphorylation. Furthermore, secondary expansion of rapamycin-regulated memory CTLs in IL-12 receptor knockouts is impaired and resultant secondary memory CTLs are abolished. This indicates that interplay between cytokines and adjuvants should be considered during vaccine design.