Type I Interferons Protect T Cells against NK Cell Attack Mediated by the Activating Receptor NCR1

Direct type I interferon (IFN) signaling on T cells is necessary for the proper expansion, differentiation, and survival of responding T cells following infection with viruses prominently inducing type I IFN. The reasons for the abortive response of T cells lacking the type I IFN receptor (Ifnar1−/−) remain unclear. We report here that Ifnar1−/− T cells were highly susceptible to natural killer (NK) cell-mediated killing in a perforin-dependent manner. Depletion of NK cells prior to lymphocytic choriomeningitis virus (LCMV) infection completely restored the early expansion of Ifnar1−/− T cells. Ifnar1−/− T cells had elevated expression of natural cytotoxicity triggering receptor 1 (NCR1) ligands upon infection, rendering them targets for NCR1 mediated NK cell attack. Thus, direct sensing of type I IFNs by T cells protects them from NK cell killing by regulating the expression of NCR1 ligands, thereby revealing a mechanism by which T cells can evade the potent cytotoxic activity of NK cells. [Display omitted] •Ifnar1−/− T cells show abortive expansion following LCMV infection•Activated Ifnar1−/− T cells are killed in a perforin-dependent manner by NK cells•Activated Ifnar1−/−, but not WT T cells, upregulate ligands for NCR1•NK cells kill activated Ifnar1−/− T cells via NCR1 engagement During some viral infections, the ability to respond to type I interferons (IFN-I) on virus-specific T cells is critical to sustain their expansion, but the reason for this dependence has been unclear. Crouse et al. demonstrate that IFN-I signaling prevents recognition and cytolysis of the T cells by NK cells via the activating receptor NCR1.