Negative T-cell regulation through programmed cell death 1 (PD-1)-programmed death ligand 1 (PD-L1) ligation is well described during viral infection; however, our understanding of the contribution of PD-L1-intrinsic signaling to antiviral immunity is limited. Herein, we show that mutation of the PD-L1 intracellular domain results in a dysregulated type 1 interferon (IFN) response in dendritic cells (DCs), sustained DC activation, and higher skin DC retention during vaccinia virus (VV) scarification of the ear. Consequently, in mice with a mutation in the cytoplasmic domain of PD-L1, we observed decreased CD8+ T-cell responses in the lymph node with enhanced CD8+ T-cell proliferation and cytokine production in the tissue. Eliminating the effect of decreased DC migration to the draining lymph node with systemic VV inoculation resulted in increased CD8+ T-cell responses after a subsequent local infection of the ear tissue. Responding CD8+ T cells in the ear displayed an increased ability to produce IFN-γ that was dependent on cDC1s. During VV rechallenge in the mice with a mutation in the cytoplasmic domain of PD-L1, the local memory CD8+ T cells showed increased cytokine production, concurrent with increased tissue swelling. Taken together, these findings establish PD-L1-intrinsic signaling as an important regulator of DC activation and migration and defines the consequences for increased T-cell residency and activity in the tissue in the absence of PD-L1-intrinsic signals.
Kantheti et al. (Sun,) studied this question.