Research Article: Tracking KLRC2 (NKG2C)+ memory-like NK cells in SIV+ and rhCMV+ rhesus macaques

Date Published: May 31, 2018

Publisher: Public Library of Science

Author(s): Daniel R. Ram, Cordelia Manickam, Brady Hueber, Hannah L. Itell, Sallie R. Permar, Valerie Varner, R. Keith Reeves, Guido Silvestri.


Natural killer (NK) cells classically typify the nonspecific effector arm of the innate immune system, but have recently been shown to possess memory-like properties against multiple viral infections, most notably CMV. Expression of the activating receptor NKG2C is elevated on human NK cells in response to infection with CMV as well as HIV, and may delineate cells with memory and memory-like functions. A better understanding of how NKG2C+ NK cells specifically respond to these pathogens could be significantly advanced using nonhuman primate (NHP) models but, to date, it has not been possible to distinguish NKG2C from its inhibitory counterpart, NKG2A, in NHP because of unfaithful antibody cross-reactivity. Using novel RNA-based flow cytometry, we identify for the first time true memory NKG2C+ NK cells in NHP by gene expression (KLRC2), and show that these cells have elevated frequencies and diversify their functional repertoire specifically in response to rhCMV and SIV infections.

Partial Text

Although NK cells have traditionally been thought to be innate immune cells that lack the antigen-specificity seen in the adaptive immune system, NK cells have very recently been reported to possess memory and memory-like functions [1–8]. Though this area of investigation is currently developing, subpopulations of NK cells that express NKG2C (CD159C) in humans or Ly49H and Ly49P in mice mobilize in response to CMV infection [9–13]. While this phenomenon has been described in human and murine studies, because of technical limitations it has not yet been possible to examine memory and memory-like NKG2C+ NK cells in NHP models. This is predominantly attributed to the high degree of homology in NHP between the extracellular domains of two NKG2 isoforms, activating NKG2C and inhibitory NKG2A –making the two indistinguishable via currently available antibodies and standard measurements [14, 15]. NHP models are crucial to multiple areas of medical research, including HIV and CMV infectious disease study and transplant biology [16–18] since the murine system does not always approximate human immunology. As such, the inability to study NKG2C+ memory NK cells in NHP models remains a major research deficit.