Licensed NK-mediated response to murine cytomegalovirus specifically upregulates dendritic cell co-stimulatory ligands required in T cell priming (VIR1P.963)

Abstract

Abstract Ly49G2+ (G2+) NK cells mediate murine (M)CMV resistance in mice with the self-MHC Dk ligand expressed. A prior study showed that G2+ NK-mediated MCMV resistance resulted in increased numbers of conventional dendritic cells (cDC) and virus-specific CD8 T cells after infection, independent of CD4 T cells. However, the molecular basis underlying licensed NK-mediated enhancement of T-cell immunity is unknown. Here we examined the role of co-stimulatory ligands expressed in splenic cDC after MCMV infection. An increase in the intracellular expression of both CD86 and CD70 was observed by 72-hr, first in the CD8α+ DC and then in the CD11b+ DC. To test functionality, we used CD86 and CD70 mAbs to block co-stimulation before infection. CD86-block had no effect on CD8 T cells. In contrast, CD70-block impaired both the frequency and the numbers of MCMV-specific CD8 T cells without perturbing cDC numbers, cDC maturation, or G2+ NK-mediated viral control. We next examined the importance of CD70-CD27 signaling in CD27-/- mice with the self-ligand Dk expressed. We observed similar deficits in Ag-specific CD8 T cells, despite having intact G2+ NK-mediated MCMV control. Moreover, CD8 T cells in both CD70-blocked and CD27-/- infected mice responded to MCMV peptide re-stimulation with less degranulation and cytokine production. We infer that a licensed G2+ NK-mediated response to MCMV upregulates co-stimulatory molecule expression in cDC that is needed to efficiently prime CD8 T cells.