152: CD8 T cell responses correlate with antigen but are independent of type I IFN and STING signaling after adenoviral vaccination

Abstract

Aims Replication deficient adenoviral (rAd) vectors are the most potent recombinant vaccines for inducing CD8 T cell responses in humans. Several vectors derived from different species and distinct serotypes are being evaluated for HIV, Tuberculosis and Malaria but their potency can vary. We therefore aimed to define in vivo innate mechanisms that modulate induction of CD8 T cell responses with rAd vectors. Methods Using 7 human-, chimp- or simian-derived rAd vectors encoding SIV Gag as a model antigen, we first comprehensively characterised CD8 T cell responses and protective efficacy in mice. We then tracked antigen expression using RT-PCR or eGFP-expressing vectors and profiled innate gene activation using microarray in the draining lymph node (dLN), to identify candidate innate pathways that influence CD8 T cell immunity. Results While the highest CD8 T cell responses were observed after vaccination with rAd vectors with high expression of antigen, the level of antigen expression inversely correlated with innate immune responses. Upon interrogation of candidate innate genes, augmenting type I IFN signaling decreased antigen expression while abrogating type I IFN signaling increased antigen expression and promoted early CD8 T cell expansion. More specifically and upstream of type I IFN induction, deficiency in STING but not RLR signaling pathways increased antigen expression and CD8 T cell expansion. Conclusions These data illustrate a reciprocal relationship between antigen expression and innate immune responses for CD8 T cell immunity and provide a mechanistic target for optimising rAd immunogenicity.