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NKG2C Natural Killer Cells in Bronchoalveolar Lavage Are Associated With Cytomegalovirus Viremia and Poor Outcomes in Lung Allograft Recipients

Calabrese, Daniel R., MD1; Chong, Tiffany, BS1; Wang, Angelia, BS1; Singer, Jonathan P., MD1; Gottschall, Marc, BS2; Hays, Steven R., MD1; Golden, Jeffrey A., MD1; Kukreja, Jasleen, MD3; Lanier, Lewis L., PhD4; Tang, Qizhi, PhD3; Greenland, John R., MD, PhD1,5

doi: 10.1097/TP.0000000000002450
Original Basic Science—General
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Background. Cytomegalovirus (CMV) infection is a risk factor for chronic lung allograft dysfunction (CLAD), which limits survival in lung allograft recipients. Natural killer (NK) cells that express the NKG2C receptor mediate CMV-specific immune responses. We hypothesized that NKG2C+ NK cells responding to CMV in the lung allograft would reduce CMV-related inflammation and would improve CLAD-free survival.

Methods. We prospectively followed 130 subjects who underwent lung transplantation from 2012 to 2016. Bronchoalveolar lavage (BAL) NK cells were immunophenotyped for NKG2C, maturation, and proliferation markers. CMV viral load, serologies, serial spirometry, and mortality were recorded from medical records. Natural killer cell subset association with CMV endpoints were made using generalized estimating equation-adjusted linear models. BAL NKG2C+ NK cell association with CLAD-free survival was assessed by Cox proportional hazards modeling.

Results. NKG2C+ NK cells were more mature and proliferative than NKG2C NK cells and represented a median of 7.8% of BAL NK cells. The NKG2C+ NK cell proportion increased prior to the first detection of viremia and was nearly tripled in subjects with high level viremia (>1000 copies/mL) compared with no detected viremia. Subjects with increased BAL NKG2C+ NK cells, relative to the median, had a significantly increased risk for CLAD or death (hazard ratio, 4.2; 95% confidence interval, 1.2–13.3).

Conclusions. The BAL NKG2C+ NK cell proportion may be a relevant biomarker for assessing risk of CMV viremia and quantifying potential CMV-related graft injury that can lead to CLAD or death.

1Department of Medicine, University of California, San Francisco, CA.

2Department of Clinical Lab Immunology, University of California, San Francisco, CA.

3Department of Surgery, University of California, San Francisco, CA.

4Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA.

5Medical Service, Veterans Affairs Health Care System, San Francisco, CA.

Received 15 June 2018. Revision received 29 August 2018.

Accepted 31 August 2018.

ORCIDS: DRC 0000-0002-0596-3434, JPS 0000-0003-0224-7472, JRG 0000-0003-1422-8367.

The authors declare no conflicts of interest.

Project funding came from award number IK2CX001034 from the Clinical Sciences Research & Development Service of the VA Office of Research and Development, the UCSF Nina Ireland Program for Lung Health (NIPLH), and a NHLBI award number R01 HL134851.

D.R.C. and J.R.G. participated in research design, article writing, performance of research, and data analysis. J.A.G., J.K., S.R.H., L.L.L., Q.T., and J.P.S. participated in research design, interpretation of the results, and article editing. T.C., A.W., and M.G. participated in performance of research.

Correspondence: John R. Greenland, San Francisco VA Medical Center, 4150 Clement St, San Francisco, CA 94121. (john.greenland@ucsf.edu).

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