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

doi:10.1016/j.celrep.2018.11.020

CMV Primes Functional Alternative Signaling in Adaptive Δg NK Cells but Is Subverted by Lentivirus Infection in Rhesus Macaques

Cell Rep. 2018 Dec 4;25(10):2766-2774.e3. doi: 10.1016/j.celrep.2018.11.020.

Authors

Spandan V Shah¹, Cordelia Manickam¹, Daniel R Ram¹, Kyle Kroll¹, Hannah Itell², Sallie R Permar², Dan H Barouch³, Nichole R Klatt⁴, R Keith Reeves⁵

Affiliations

¹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
² Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
³ 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.
⁴ 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.
⁵ 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. Electronic address: rreeves@bidmc.harvard.edu.

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.

Keywords: CMV; HIV; SIV; innate immunity; natural killer cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity*
Alternative Splicing / genetics*
Animals
Cytomegalovirus / physiology*
Female
Killer Cells, Natural / metabolism*
Lentivirus / physiology*
Macaca mulatta
Male
Mucous Membrane / immunology
Receptors, Fc / metabolism*
Simian Acquired Immunodeficiency Syndrome / immunology
Simian Acquired Immunodeficiency Syndrome / virology
Simian Immunodeficiency Virus / immunology

Substances

Receptors, Fc

Abstract

Publication types

MeSH terms

Substances

Grants and funding