NKG2C natural killer cells in bronchoalveolar lavage are associated with cytomegalovirus viremia and poor outcomes in lung allograft recipients

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. NK 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 (HR 4.2, 95% CI 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. Correspondence and reprint requests to Dr. John R. Greenland, San Francisco VA Medical Center, 4150 Clement St, San Francisco, CA 94121, USA; 415-221-4810x22962, john.greenland@ucsf.edu ORCIDS: DRC 0000-0002-0596-3434, JPS 0000-0003-0224-7472, JRG 0000-0003-1422-8367 FUNDING 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 DISCLOSURES The authors of this manuscript have no conflicts of interest to disclose. AUTHORSHIP CONTRIBUTIONS DRC and JRG participated in research design, manuscript writing, performance of research, and data analysis. JAG, JK, SRH, LLL, QT, and JPS participated in research design, interpretation of the results, and manuscript editing. TC, AW, and MG participated in performance of research. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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