Human Cytomegalovirus (CMV)-Induced Memory-like NKG2C+ NK Cells Are Transplantable and Expand In Vivo in Response to Recipient CMV Antigen

We have previously shown that NKG2C(+) NK cells from CMV naive umbilical cord blood grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation. In this study, recipients of adult donor hematopoietic cell transplantation were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C(+) NK cells to determine responses to secondary CMV events. Expansion of NKG2C(+) NK cells was seen following clinical CMV reactivation. However, they also expanded in the absence of detectable CMV viremia when both the donor and recipient were CMV seropositive. Upregulation of NKG2C was observed in NK cells from CMV-positive recipients receiving grafts from CMV-seropositive or -seronegative donors. These in vivo-expanded NKG2C(+) NK cells had an increased capacity for target cell-induced cytokine production, expressed an inhibitory killer Ig-like receptor for self-HLA and preferentially acquired CD57. Most importantly, NKG2C(+) NK cells transplanted from seropositive donors exhibit heightened function in response to a secondary CMV event compared with NKG2C(+) NK cells from seronegative donors. We conclude that NKG2C(+) memory-like NK cells are transplantable and require active or latent (subclinical) expression of CMV Ag in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.