Rabbit Anti-Human HLA-E Polyclonal antibody

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 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.

A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of 'missing-self' recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here, we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, pQa-1 selectively inhibits NKG2A(+) NK cells and expression of pQa-1 can protect tumor cells from NK control in vivo. Collectively, these findings reveal an innovative NK evasion strategy wherein RHVP encodes a modified Qa-1 mimic refractory to MHC-I sabotage and capable of specifically engaging inhibitory receptors to circumvent NK activation.