NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner

A better understanding of mechanisms that regulate CD8(+)T cell responses to therapeutic vaccines is needed to develop approaches to enhance vaccine efficacy for chronic viral infections and cancers. We show here that NK cell depletion enhanced antigen-specific T cell responses to chimp adenoviral vector (ChAdOx) vaccination in a mouse model of chronic HBV infection (CHB). Probing the mechanism underlying this negative regulation, we observed that CHB drove parallel up-regulation of programmed cell death ligand 1 (PD-L1) on liver-resident NK cells and programmed cell death 1 (PD-1) on intrahepatic T cells. PD-L1-expressing liver-resident NK cells suppressed PD-1(hi)(C)D8(+)T cells enriched within the HBV-specific response to therapeutic vaccination. Cytokine activation of NK cells also induced PD-L1, and combining cytokine activation with PD-L1 blockade resulted in conversion of NK cells into efficient helpers that boosted HBV-specific CD8(+)T cell responses to therapeutic vaccination in mice and to chronic infection in humans. Our findings delineate an immunotherapeutic combination that can boost the response to therapeutic vaccination in CHB and highlight the broader importance of PD-L1-dependent regulation of T cells by cytokine-activated NK cells.

Automated summary

This study demonstrates that NK cell depletion enhances the immune response to vaccines in a mouse model of chronic HBV infection. It was found that the up-regulation of PD-L1 on liver-resident NK cells and PD-1 on intrahepatic T cells plays a negative regulatory role in the response to therapeutic vaccination. Combining cytokine activation with PD-L1 blockade can convert NK cells into efficient helpers, boosting the CD8(+) T cell response to therapeutic vaccination.