Dynamic Changes in Natural Killer Cell Subset Frequencies in the Absence of Cytomegalovirus Infection.

Ivayla E Gyurova,Lilliam Ambroggio,Hannah Than Win,Stephen N Waggoner,Heinrich Schlums,Yenan T Bryceson,Heidi Sucharew,David E Ochayon,David I Bernstein

doi:10.3389/fimmu.2019.02728

Abstract

Individuals lacking functional natural killer (NK) cells suffer severe, recurrent infections with cytomegalovirus (CMV), highlighting the critical role of NK cells in antiviral defense. Therefore, ongoing attempts to develop an efficacious vaccine to prevent CMV infection should potentially aim to elicit NK-cell antiviral responses as an accessory to conventional T- and B-cell based approaches. In this regard, CMV infection provokes marked phenotypic and functional differentiation of the NK-cell compartment, including development of adaptive NK cells that exhibit enhanced antiviral activity. We examined longitudinal blood samples collected from 40 CMV-seronegative adolescents to ascertain whether a CMV glycoprotein B (gB) vaccine in the absence of CMV infection can stimulate differentiation or expansion of CMV-associated subsets of NK cells. Study participants uniformly lacked the CMV-dependent NKG2C+ subset of NK cells, suggesting that an adjuvanted CMV gB vaccine alone is an inadequate stimulus for sustained expansion of these cells. In contrast, we observed unexpected dynamic fluctuations in the frequency of NK cells lacking FcRγ, EAT-2, and SYK, which were independent of vaccination or CMV infection. Whereas, FcRγneg NK cells in CMV infection are reported to express increased levels of the maturation marker CD57, the FcRγneg NK cells observed in our CMV-negative vaccine cohort express less CD57 than their FcRγ+ counterparts. The FcRγneg NK cells in CMV-negative individuals were also functionally distinct from this subset in CMV infection, exhibiting comparable IFN-γ production and degranulation as FcRγ+ NK cells in response to cytokine or antibody-dependent stimuli. These results suggest that frequencies of some NK cell subsets may increase in response to unknown environmental or inflammatory cues distinct from that which occurs after CMV infection. Greater understanding of the nature of the signals driving CMV-independent accumulation of these subsets should permit development of mechanisms to facilitate vaccine-driven expansion of CMV-reactive NK cells.

Highlights

Cytomegalovirus (CMV) is a significant global cause of morbidity with manifestations of infection ranging from subclinical disease to death
To determine whether CMV vaccination strategies can trigger emergence of CMV-associated Natural killer (NK) cell subsets, we examined a longitudinal series of peripheral blood mononuclear cell (PBMC) from a subset (n = 40, Table 1) of CMV vaccine trial participants (NCT00133497) for whom a full set of samples were available
We first assessed the proportion of total NK cells (CD56+ CD3− CD19− CD14− CD4−) in PBMC

Summary

Introduction

Cytomegalovirus (CMV) is a significant global cause of morbidity with manifestations of infection ranging from subclinical disease to death. The same vaccine conferred short-lived, 50% protection, against CMV infection in seronegative post-partum women [4] and reduced post-transplant viral load when given to patients awaiting a kidney or liver transplant [5] While promising, these results indicate that humoral responses against gB may be insufficient to effectively prevent CMV infection in many individuals. DNA vaccines aimed at eliciting CMV-reactive T cells have afforded minimal protection in a transplant patient-based clinical trial [6] These advances prompted development of new vaccines aimed at eliciting both humoral and cellular immunity [7], but it remains unclear whether other arms of the immune response must be engaged to effectively prevent CMV infection

Methods

Results

Conclusion