Abstract
Despite burgeoning evidence demonstrating the adaptive properties of natural killer (NK) cells, mechanistic data explaining these phenomena are lacking. Following antibody sensitization, NK cells lacking the Fc receptor (FcR) signaling chain (Δg) acquire adaptive features, including robust proliferation, multifunctionality, rapid killing, and mobilization to sites of virus exposure. Using the rhesus macaque model, we demonstrate the systemic distribution of Δg NK cells expressing memory features, including downregulated Helios and Eomes. Furthermore, we find that Δg NK cells abandon typical γ-chain/Syk in lieu of CD3ζ-Zap70 signaling. FCγRIIIa (CD16) density, mucosal homing, and function are all coupled to this alternate signaling, which in itself requires priming by rhesus cytomegalovirus (rhCMV). Simian immunodeficiency virus (SIV) infections further expand gut-homing adaptive NK cells but result in pathogenic suppression of CD3ζ-Zap70 signaling and function. Herein, we provide a mechanism of virus-dependent alternative signaling that may explain the acquisition of adaptive features by primate NK cells and could be targeted for future vaccine or curative therapies.
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•Δg NK cell expansion and acquisition of function are driven by concurrent CMV infection•Δg NK cells are distributed systemically but have the propensity to migrate to mucosal sites•Δg NK cells abandon γ-chain/Syk signaling in lieu of the atypical CD3ζ-Zap70 signaling pathway•SIV infection subverts Δg NK cells by suppressing CD16-mediated CD3ζ-ZAP70 signaling
Gamma-chain-deficient adaptive NK cells are robust mediators of antiviral immunity via ADCC. Shah et al. demonstrate using macaque models that acquisition of these features requires previous priming with CMV infection and involves alternative signaling via CD3zeta but is actively suppressed by lentivirus infection.
