Enrichment of cytomegalovirus-induced NKG2C+ Natural Killer cells in the lung allograft

Background In lung transplant recipients, immunosuppressive medications result in impaired antiviral immunity and a propensity for cytomegalovirus (CMV) reactivation within the lung allograft. Natural Killer (NK) cells play a key role in immunity to CMV, with an increase in the proportion of NK cells expressing activating CD94-NKG2C receptors in the blood being a strong correlate of CMV infection. Whether a similar increase in NKG2C+ NK cells occurs in lung transplant recipients following CMV reactivation in the allograft and if such cells contribute to viral control, remains unclear. Methods In this pilot study, we longitudinally assessed the frequency and phenotype of NKG2C+ NK cells in the blood and bronchoalveolar lavage (BAL) of lung transplant recipients and stratified recipients based on their risk of developing CMV disease. Results We observed an increase in the proportion of NKG2C+ NK cells in the blood and BAL of CMV high-risk patients, coincident with both the cessation of anti-viral prophylaxis and subsequent detection of actively replicating CMV in the blood and/or lung allograft. Additionally, these NKG2C+ NK cells expressed killer-cell immunoglobulin-like receptors (KIR) distinct from those of other NK subsets and BAL NKG2C+ NK cells possessed an activated phenotype. Finally, the frequency of NKG2C+ NK cells in the BAL may be inversely correlated with CMV blood titers. Conclusions Monitoring the phenotype of NK cells post-lung transplant may be a useful biomarker for monitoring patient levels of CMV immunity. # Joint senior authors * Corresponding author: Lucy C. Sullivan, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia Email: lcsull@unimelb.edu.au Authorship: Conceived and designed experiments: L.C.S., A.J.B., G.P.W. Performed the experiments: C.M.H., J.M.L.W., A.K., L.C.S. Analyzed the data: C.M.H, L.C.S., S.S. Contributed reagents/materials/analysis tools: Y.C., B.L., G.I.S., G.P.W. Wrote the paper: L.C.S., C.M.H., S.S., G.I.S., G.P.W. Disclosures: The authors declare no conflicts of interest Funding: National Health and Medical Research Council (NHMRC) Program Grant (A.G.W.), NHMRC Project Grant (L.C.S. and G.P.W.). We acknowledge the Margaret Pratt Foundation and the Lungitude Foundation for ongoing support. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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