Long-Term Evolution of the Adaptive NKG2C+ NK Cell Response to Cytomegalovirus Infection in Kidney Transplantation: An Insight on the Diversity of Host-Pathogen Interaction

Human CMV infection is frequent in kidney transplant recipients (KTR). Pretransplant Ag-specific T cells and adaptive NKG2C(+) NK cells associate with reduced incidence of infection in CMV+ KTR. Expansions of adaptive NKG2C+ NK cells were reported in posttransplant CMV-infected KTR. To further explore this issue, NKG2C(+) NK, CD8+, and TcR gamma delta T cells were analyzed pretransplant and at different time points posttransplant for >= 24 mo in a cohort of CMV+ KTR (n = 112), stratified according to CMV viremia detection. In cryopreserved samples from a subgroup (n = 49), adaptive NKG2C+ NK cell markers and T cell subsets were compared after a longer follow-up (median, 56 mo), assessing the frequencies of CMV-specific T cells and viremia at the last time point. Increased proportions of NKG2C+ NK, CD8+, and TcR gamma delta T cells were detected along posttransplant evolution in viremia(+) KTR. However, the individual magnitude and kinetics of the NKG2C(+) NK response was variable and only exceptionally detected among viremia(-) KTR, presumably reflecting subclinical viral replication events. NKG2C+ expansions were independent of KLRC2 zygosity and associated with higher viral loads at diagnosis; no relation with other clinical parameters was perceived. Increased proportions of adaptive NKG2C(+) NK cells (CD57(+), ILT2(+), FceRIy-) were observed after resolution of viremia long-term posttransplant, coinciding with increased CD8(+) and V delta 2(-) y delta T cells; at that stage CMV-specific T cells were comparable to viremia(-) cases. These data suggest that adaptive NKG2C(+) NK cells participate with T cells to restore CMV replication control, although their relative contribution cannot be discerned. The Journal of Immunology, 2021, 207: 1882-1890.

Automated summary

Human CMV infection is common in kidney transplant recipients, with pretransplant Ag-specific T cells and adaptive NKG2C(+) NK cells being associated with reduced infection rates. Increases in NKG2C(+) NK, CD8+, and TcR gamma delta T cells were observed posttransplant in CMV+ KTR, especially in those with viremia. After resolution of viremia, higher proportions of adaptive NKG2C(+) NK cells, along with increased CD8+ and TcR gamma delta T cells, were found, suggesting their role in restoring CMV replication control.