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Enrichment of Cytomegalovirus-induced NKG2C+ Natural Killer Cells in the Lung Allograft

Harpur, Christopher M. PhD1; Stankovic, Sanda PhD1; Kanagarajah, Abbie BMedSci1; Widjaja, Jacqueline M.L. BSc1; Levvey, Bronwyn J. RN2; Cristiano, Yvonne RN2; Snell, Greg I. MD2; Brooks, Andrew G. PhD1; Westall, Glen P. MD, PhD2; Sullivan, Lucy C. PhD1,2

doi: 10.1097/TP.0000000000002545
Original Clinical Science—General
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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 antiviral prophylaxis and subsequent detection of actively replicating CMV in the blood and lung allograft. Additionally, these NKG2C+ NK cells expressed killer-cell immunoglobulin-like receptors 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 postlung transplant may be a useful biomarker for monitoring patient levels of CMV immunity.

1 Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

2 Lung Transplant Service, The Alfred Hospital, Melbourne, VIC, Australia.

Received 31 May 2018. Revision received 21 October 2018.

Accepted 23 October 2018.

A.G.B., G.P.W., and L.C.S. are Joint senior authors.

L.C.S., A.J.B., and G.P.W. conceived and designed the experiments. C.M.H., J.M.L.W., A.K., and L.C.S. performed the experiments. C.M.H, L.C.S., and S.S. analyzed the data. Y.C., B.L., G.I.S., and G.P.W. contributed reagents/materials/analysis tools. L.C.S., C.M.H., S.S., G.I.S., and G.P.W. wrote the article.

The authors declare no conflicts of interest.

A.G.W. was supported by National Health and Medical Research Council (NHMRC) Program Grant and L.C.S. and G.P.W. were supported by NHMRC Project Grant.

Correspondence: Lucy C. Sullivan, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. (lcsull@unimelb.edu.au).

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