CMV Primes Functional Alternative Signaling in Adaptive Δg NK Cells but Is Subverted by Lentivirus Infection in Rhesus Macaques
Spandan V. Shah,
Cordelia Manickam,
Daniel R. Ram,
Kyle Kroll,
Hannah Itell,
Sallie R. Permar,
Dan H. Barouch,
Nichole R. Klatt,
R. Keith Reeves
Affiliations
Spandan V. Shah
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Cordelia Manickam
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Daniel R. Ram
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Kyle Kroll
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Hannah Itell
Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
Sallie R. Permar
Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
Dan H. Barouch
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA 02139, USA
Nichole R. Klatt
Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Miami, Miami, FL 33136, USA
R. Keith Reeves
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA 02139, USA; Corresponding author
Summary: 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. : 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. Keywords: natural killer cells, CMV, innate immunity, HIV, SIV
