NKG2C^pos NK Cells Regulate the Expansion of Cytomegalovirus-Specific CD8 T Cells

Infection with the human CMV associates with phenotypic alterations in lymphocyte subsets. A highly reproducible finding in CMV-seropositive individuals is an expansion of NKG2C^pos NK cells. In this study, we analyzed if the altered NK cell compartment in CMV-seropositive human donors may affect CMV-specific CD8 T cells. Resting CMV-specific CD8 T cells were terminally differentiated and expressed high levels of the NKG2C ligand HLA-E. Activation of CMV-specific CD8 T cells with the cognate Ag further increased HLA-E expression. In line with a negative regulatory effect of NKG2C^pos NK cells on HLA-E^high CD8 T cells, depletion of NKG2C^pos NK cells enhanced Ag-specific expansion of CMV-specific CD8 T cells in vitro. In turn, the activation of NK cells in coculture with CMV-specific CD8 T cells promoted a selective loss of HLA-E^high CD8 T cells. To test if NKG2C^pos NK cells can target HLA-E^high CD8 T cells, Jurkat T cells with and without stabilized HLA-E on the surface were used. NKG2C^pos NK cells stimulated with HLA-E^high Jurkat cells released higher levels of Granzyme B compared with NKG2C^neg NK cells and NKG2C^pos NK cells stimulated with HLA-E^low Jurkat cells. Moreover, intracellular levels of caspase 3/7 were increased in HLA-E^high Jurkat cells compared with HLA-E^low Jurkat cells, consistent with higher rates of apoptosis in HLA-E^high T cells in the presence of NKG2C^pos NK cells. Our data show that NKG2C^pos NK cells interact with HLA-E^high CD8 T cells, which may negatively regulate the expansion of CMV-specific CD8 T cells upon activation.