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 FcεRIγ or gain of NKG2C expression. Here, we investigated the heterogeneity of human CD56 NK cell subpopulations according to the expression of FcεRIγ and NKG2C in a large cohort ( = 127). Although the frequency of FcεRIγ and NKG2C NK cells positively correlated, the FcεRIγ and NKG2C NK cell populations did not exactly overlap. The FcεRIγNKG2C, FcεRIγNKG2C, and FcεRIγNKG2C NK cell populations were only evident after HCMV infection, but each had distinct characteristics. Among the subpopulations, FcεRIγNKG2C NK cells exhibited the most restricted killer immunoglobulin-like receptor repertoire, suggesting clonal expansion. Moreover, FcεRIγNKG2C NK cells exhibited the lowest Ki-67 and highest Bcl-2 expression, indicating the long-lived quiescent memory-like property. Functionally, FcεRIγNKG2C NK cells had weak natural effector function against K562 but strong effector functions by CD16 engagement, whereas FcεRIγNKG2C NK cells had strong effector functions in both settings. Anatomically, the FcεRIγNKG2C, FcεRIγNKG2C, and FcεRIγNKG2C NK cell populations were present in multiple human peripheral organs. In conclusion, we demonstrate the heterogeneity of memory-like NK cells stratified by FcεRIγ and NKG2C and suggest both markers be utilized to better define these cells.