Enhanced memory development in mice by aptamer targeted mTORC1 inhibition in CD8+ T cells (110.3)

Abstract

Abstract Recent studies have highlighted the importance of immunological memory in mediating protective immunity in chronic infectious diseases and cancer. Inhibition of intracellular mediators of T cell differentiation with pharmacological agents was shown to promote memory differentiation in mice. However, given their often pleiotropic effects, non-targeted administration of pharmacological agents could compromise their immune promoting properties. We have shown that a CD8+ T cell targeted 4-1BB aptamer -raptor siRNA conjugate downregulated mTORC1, while preserving mTORC2, activity in 60% of adoptively transferred OVA-primed OT-I cells while sparing host cells. Both rapamycin and aptamer-siRNA conjugate led to the development of an enhanced proliferative recall response. However, the rapamycin-generated memory cells were defective in their in vivo cytotoxic effector functions which correlated with reduced perforin expression. Likewise, rapamycin or aptamer-siRNA conjugate treatment enhanced the in vivo differentiation of gp100-primed Pmel-1 cells into memory cells. Consistent with a cytotoxic defect in the rapamycin-generated memory cells, the rapamycin-treated mice were not able to inhibit a challenge with gp100-expressing B16 melanoma tumor cells. These observations support the premise that in vivo cell-targeted inhibition of mTOR, and conceivably other mediators of T cell differentiation, will circumvent undesirable effects of non-targeted inhibition by pharmacological agents.