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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02728

Dynamic changes in natural killer cell subset frequencies in the absence of cytomegalovirus infection

 Ivayla E. Gyurova1, 2, Heinrich Schlums3, Heidi Sucharew4, Lilliam Ambroggio5, David Ochayon1, Hannah T. Win1,  Yenan Bryceson3, David Bernstein6, 7 and  Stephen N. Waggoner1, 2, 6*
  • 1Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, United States
  • 2University of Cincinnati, United States
  • 3Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Sweden
  • 4Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, United States
  • 5Sections of Emergency Medicine and Hospital Medicine, Children's Hospital Colorado, Department of Pediatrics, University of Colorado Denver, United States
  • 6Department of Pediatrics, College of Medicine, University of Cincinnati, United States
  • 7Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, United States

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 FcRg, EAT-2, and SYK, which were independent of vaccination or CMV infection. Whereas FcRg-neg NK cells in CMV infection are reported to express increased levels of the maturation marker CD57, the FcRg-neg NK cells observed in our CMV-negative vaccine cohort express less CD57 than their FcRg+ counterparts. The FcRg-neg NK cells in CMV-negative individuals were also functionally distinct from this subset in CMV infection, exhibiting comparable IFN-g production and degranulation as FcRg+ 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.

Keywords: CMV, NK cells, Memory, CD56, CD57, Immunization, innate lymphoid cell, FcRgamma

Received: 22 Aug 2019; Accepted: 07 Nov 2019.

Copyright: © 2019 Gyurova, Schlums, Sucharew, Ambroggio, Ochayon, Win, Bryceson, Bernstein and Waggoner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Stephen N. Waggoner, Cincinnati Children's Hospital Medical Center, Center for Autoimmune Genomics and Etiology, Cincinnati, United States, stephen.waggoner@cchmc.org