Pretransplant adaptive NKG2C+ NK cells protect against cytomegalovirus infection in kidney transplant recipients

Abstract

Cytomegalovirus (CMV) infection constitutes a complication for kidney transplant recipients (KTR) and CMV‐specific T cells reduce the risk of viral replication in seropositive patients. CMV promotes the adaptive differentiation and expansion of an NK cell subset, hallmarked by expression of the CD94/NKG2C receptor with additional characteristic features. We previously reported an association of pretransplant NKG2C+ NK cells with a reduced incidence of CMV infection. We have strengthened the analysis in cryopreserved peripheral blood mononuclear cells from an enlarged KTR cohort (n = 145) with homogeneous immunosuppression, excluding cases at low risk of infection (ie, CMV D−R−) or receiving antiviral prophylaxis. Moreover, adaptive NKG2C+ NK cell–associated markers (ie, NKG2A, CD57, Immunoglobulin‐like transcript 2 [LIR1 or LILRB1], FcεRI γ chain, and Prolymphocytic Leukemia Zinc Finger transcription factor) as well as T lymphocyte subsets were assessed by multicolor flow cytometry. The relation of NKG2C+ NK cells with T cells specific for CMV antigens was analyzed in pretransplant patients (n = 29) and healthy controls (n = 28). Multivariate Cox regression and Kaplan‐Meier analyses supported that NKG2C+ NK cells bearing adaptive markers were specifically associated with a reduced incidence of posttransplant symptomatic CMV infection; no correlation between NKG2C+ NK cells and CMV‐specific T cells was observed. These results support that adaptive NKG2C+ NK cells contribute to control CMV infection in KTR.

Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

“…This suggests that the severity of CMV disease influences the expansion of adaptive NK cells but also raises the possibility that adaptive NK cells may play a role in controlling the severity of CMV disease. Similarly, in the context of SOT, adaptive NK cells have been associated with reduced incidence of CMV viraemia in kidney transplant recipients [ 61 ]. Conversely, increased proportions of adaptive NK cells in bronchial lavage fluid has been associated with chronic lung allograft dysfunction and even death, suggesting that adaptive NK cells responding to CMV infection may cause considerable life-threatening collateral damage in transplant recipients.…”

Reduced expansion of CD94/NKG2C+ NK cells in chronic lymphocytic leukemia and CLL‐like monoclonal B‐cell lymphocytosis is not related to increased human cytomegalovirus seronegativity or NKG2C deletions

“…Immunocompromised patients show an expansion of CD94/NKG2C + NK cells inversely correlated to the efficacy of the T‐cell response against the virus, suggesting that this subset might act as a compensatory mechanism in anti‐viral defense 19 . In this line, a role of CD94/NKG2C + cells in controlling HCMV infection in kidney transplantation recipients has been recently reported 26 . To the best of our knowledge, the expression of NKG2C in MBL and CLL has been poorly investigated.…”

The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation

“…In particular the presence after Cytomegalovirus infection of a specific subset of mature NK cells expressing the CD94/NKG2Cactivating receptor can control the viral infection in kidney transplant recipients (104,105).…”

“…Activated KIR genes have been associated with the protection from human Cytomegalovirus infection in renal transplantation ( 85 ), an infection associated with graft loss and reduced survival. In particular the presence after Cytomegalovirus infection of a specific subset of mature NK cells expressing the CD94/NKG2C-activating receptor can control the viral infection in kidney transplant recipients ( 104 , 105 ).…”