Circulating NKG2A–NKG2D+ CD56dimCD16+ Natural Killer (NK) Cells as Mediators of Functional Immunosurveillance in Kidney Transplant Recipients

BACKGROUND: Recently, in patients with long-term functioning allografts, we showed that high NKG2D+ NK cell numbers in the peripheral blood were associated with a higher glomerular filtration rate, whereas high NKG2A+ NK cells were associated with a lower glomerular filtration rate. Both NK cell determinants react with ligands (MIC A/B, HLA-E) expressed on stressed cells, such as virus-infected cells, tumor cells, or cells activated during graft rejection. In the present study, we attempted to characterize these 2 NK cell subsets further. MATERIAL/METHODS: Using flow cytometry, NK cell subsets were analyzed in whole-blood samples of 35 stable kidney transplant recipients (serum creatinine mean±SD: 1.44±0.45 mg/dl). Blood was obtained 95–3786 days after transplant (mean±SD: 1168±1011 days after transplant). RESULTS: High proportions of NKG2A–NKG2D+ NK cells were strongly associated with high numbers of CD56dimCD16+ (p=0.001) NK cells co-expressing CD107 (P=0.001) and granzyme B (P=0.045), suggesting that NKG2A–NKG2D+ NK cells are predominantly cytotoxic. In contrast, high numbers of NKG2A+NKG2D− NK cells were strongly associated with low numbers of CD56dimCD16+ NK cells expressing CD107 (P=0.026), CD25 (p=0.008), TGF-βR (P=0.028), and TGF-β (P=0.005), suggesting that patients with high proportions of NKG2A+NKG2D− NK cells have low proportions of NK cell subsets with cytotoxic phenotype. CONCLUSIONS: A high proportion of NKG2A+NKG2D− NK cells is associated with decreased counts of NKG2A–NKG2D+ CD56dimCD16+ cytotoxic NK cells in the circulation. This may result in impaired immunosurveillance. We would like to hypothesize that NKG2A–NKG2D+ CD56dimCD16+ cytotoxic NK cells eliminate MIC A/B-expressing stressed cells which possess a potential to harm the transplant. Further studies will have to evaluate whether the proportion of NKG2A–NKG2D+ CD56dimCD16+ cytotoxic NK cells is a useful biomarker for the prediction of an uncomplicated postoperative course in kidney transplant recipients.