Phenotypic and Functional Analysis of Human NK Cell Subpopulations According to the Expression of FcεRIγ and NKG2C

Human memory-like NK cells are commonly defined by either a lack of Fc epsilon RI gamma or gain of NKG2C expression. Here, we investigated the heterogeneity of human CD56(dim) NK cell subpopulations according to the expression of Fc epsilon RI gamma and NKG2C in a large cohort (n = 127). Although the frequency of Fc epsilon RI gamma(-) and NKG2C(+) NK cells positively correlated, the Fc epsilon RI gamma(-) and NKG2C(+) NK cell populations did not exactly overlap. The Fc epsilon RI gamma(+)NKG2C(+), Fc epsilon RI gamma(-)NKG2C(+), and Fc epsilon RI gamma(-)NKG2C(-) NK cell populations were only evident after HCMV infection, but each had distinct characteristics. Among the subpopulations, Fc epsilon RI gamma(-)NKG2C(+) NK cells exhibited the most restricted killer immunoglobulin-like receptor repertoire, suggesting clonal expansion. Moreover, Fc epsilon RI gamma(-)NKG2C(+) NK cells exhibited the lowest Ki-67 and highest Bcl-2 expression, indicating the long-lived quiescent memory-like property. Functionally, Fc epsilon RI gamma(-)NKG2C(+) NK cells had weak natural effector function against K562 but strong effector functions by CD16 engagement, whereas Fc epsilon RI gamma(+)NKG2C(+) NK cells had strong effector functions in both settings. Anatomically, the Fc epsilon RI gamma(+)NKG2C(+), Fc epsilon RI gamma(-)NKG2C(+), and Fc epsilon RI gamma(-)NKG2C(-) NK cell populations were present in multiple human peripheral organs. In conclusion, we demonstrate the heterogeneity of memory-like NK cells stratified by Fc epsilon RI gamma and NKG2C and suggest both markers be utilized to better define these cells.