Increased NKG2C+ Natural Killer Cells in Bronchoalveolar Lavage Precede CMV Viremia and Are Associated with CLAD or Death in Lung Transplant Recipients

Abstract

Purpose Cytomegalovirus (CMV) mediates clinical outcomes in lung allograft recipients. The NKG2C receptor on natural killer (NK) cells is encoded by the KLRC2 gene and recognizes CMV with memory-like capabilities. We hypothesized that NKG2C+ NK cells in bronchoalveolar lavage (BAL) would be associated with CMV burden and decreased chronic lung allograft dysfunction (CLAD)-free survival. Methods BAL cells were prospectively collected from 130 lung transplant recipients at a single center, with a median 391 days follow up time. NKG2C+ and - NK cell populations in BAL were compared for markers of maturation (NKG2A, CD16, KIR), propagation (Ki67), and KLRC2 genotype (rs2734561) by Student's t-test or ANOVA. CMV viremia was defined as negative, low ( 1000 copies/mL). NKG2C+ NK cell association with CMV viremia was determined using generalized linear modeling, and association with CLAD-free survival was determined by Cox proportional hazards models adjusted for transplant characteristics, KLRC2genotype, CMV viremia, and CMV serostatus. Results BAL NKG2C+ NK cells were more mature (NKG2A-CD16+, 25.8% vs 18.4%, p Conclusion BAL NKG2C+ NK cells were more mature than NKG2C- NK cells and expression differed between KLRC2 genotypes. NKG2C+ NK cells increased prior to viremia and higher NKG2C+ NK cell frequencies were associated with worse CLAD-free survival. Measurement of NKG2C+ NK cells in BAL may be a useful tool for assessing CMV disease burden in this population.