Adaptive NKG2C+ NK Cell Response and the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients

Abstract

CMV infection in kidney transplant recipients (KTRs) has been associated with an increased risk for graft loss and reduced host survival. CMV promotes persistent expansions of NK cells expressing the CD94/NKG2C receptor. The NKG2C (KLRC2) gene is frequently deleted, and copy number influences the adaptive response of NKG2C NK cells. The distribution of NKG2C NK cells and NKG2C genotypes (NKG2C, NKG2C, NKG2C) were studied in cross-sectional (n = 253) and prospective (n = 122) KTR cohorts. Assessment of CMV viremia was restricted to symptomatic cases in the retrospective study, but was regularly monitored in the prospective cohort. Overall, the proportions of NKG2C NK cells were significantly higher in KTRs who had suffered posttransplant symptomatic CMV infection in the cross-sectional study. Yet, along the prospective follow-up (3, 6, 12, and 24 mo), posttransplant NKG2C NK cell expansions were not observed in every patient with detectable viremia who received preemptive antiviral therapy, suggesting that the adaptive NK cell response may be inversely related with the degree of CMV control. Remarkably, the incidence of posttransplant viremia was reduced among cases with high pretransplant levels of NKG2C NK cells. The NKG2C genotype distribution was comparable in KTR and healthy controls, and greater proportions of NKG2C cells were detected in NKG2C than in NKG2C patients. Yet, a trend toward increased NKG2C and reduced NKG2C frequencies associated with symptomatic infection was appreciated in both cohorts. Altogether, our results indirectly support that adaptive NKG2C NK cells are involved in the control of CMV in KTRs.

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

“…CMV infections were categorized as asymptomatic (n = 22) or symptomatic (n = 26), with the latter including 5 cases with tissue‐invasive disease. In line with previous reports, the incidence of CMV viremia (33%) was significantly related to increasing age and appeared to be decreased in the group transplanted from living donors (22.1%) …”

“…Studies were conducted in a selected cohort of KTR (n = 145) ( Table 1) In line with previous reports, the incidence of CMV viremia (33%) was significantly related to increasing age 35 and appeared to be decreased in the group transplanted from living donors (22.1%). 42…”

“…Adaptive NKG2C NK cells are absent in CMV− individuals and thus cannot prevent primary infection in CMV D+ R− cases. However, whether they play an antiviral function following their expansion in response to posttransplant CMV infection and in CMV+ KTR treated with lymphocyte‐depleting antibodies deserves attention.…”

“…34 Finally, in a pilot study we reported an association of pretransplant levels of total NKG2C+ NK cells with a reduced incidence of CMV viremia in KTR. 35 In the present study we extended the analysis, enlarging the cohort and introducing additional adaptive NK cell markers, to discern their role in protection against CMV infection and their relation to the T cell response.…”

NK cell and Th17 responses are differentially induced in murine cytomegalovirus infected renal allografts and vary according to recipient virus dose and strain

“…Initial control of primary CMV infection is mediated by natural killer (NK) cells (10–12). Among transplant patients, NK cells increase in number and activation status during episodes of HCMV viremia, and NK cells with activating receptors are enriched in peripheral blood during CMV infection (13–17). Patients with NK activating killer cell immunoglobulin-like receptor (KIR) genotypes have lower rates of post-transplant HCMV infection (15, 17, 18).…”