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

Abstract

We have previously shown that NKG2C+ NK cells from CMV naïve umbilical cord blood (UCB) grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation (HCT). In this study, recipients of adult donor HCT were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C+ NK cells in order 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 KIR 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 to 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 antigen in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.

Natural killer cell memory in infection, inflammation and cancer

“…Subsequent studies of patients who were infected by HCMV or in whom the virus was reactivated owing to immunosuppression after solid organ or haematop oietic stem cell transplantation confirmed that the CD94-NKG2C + NK cell population preferentially expands during acute HCMV infection, subsequently persist as memory cells and can constitute up to 70% of the total NK cell population in some individuals [34][35][36] . Moreover, after haematopoietic stem cell transplantation, CD94-NKG2C + NK cells from HCMV-seropositive donors demonstrated enhanced function in response to re-exposure to HCMV in HCMV-seropositive recipients whereas CD94-NKG2C + NK cells from HCMVseronegative donors did not, suggesting the existence of a memory response against HCMV infection 37 . In in vitro experiments in which HCMV-infected fibroblasts were co-cultured with NK cells either knocked down for HLA-E by short hairpin RNA or treated with CD94-or NKG2C-specific blocking antibodies 38 , the interaction of CD94-NKG2C with its ligand HLA-E 39 was shown to drive the expansion of the CD94-NKG2C + NK cell population (FIG.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…CMV also skews the NK cell receptor repertoire in humans, with cells expressing the activating heterodimer NKG2C/CD94 expanding in recipients of solid organ74 or umbilical cord blood (UCB) transplantation75 during primary CMV infection or reactivation. These cells have an enhanced ability to secrete IFN γ in response to target cells or, even more so, upon CMV reactivation 74, 75, 76. Therefore, it has been suggested that these cells represent the human counterparts of Ly49H+ NK cells with memory‐like properties.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…NK cells acquire a mature phenotype CD56+ (CD56 dim ) during CMV activation (178). In solid organ transplant patients, acute CMV infection increases the CD57+ NKGDC hi (memory phenotype) pool, which appears to be CMV specific (179).…”

“…In early stages of CMV infection, CMV binding of TLR2 and the CD14 cofactor on monocytes trigger inflammatory cytokine production via activation of NF-kB (173 NK cell activation in the early host responses to CMV manifests with IFN-c production, direct cytotoxicity and ADCC (178). NK cells acquire a mature phenotype CD56+ (CD56 dim ) during CMV activation (178).…”