Introduction Disease association studies have shown that the inhibitory killer cell immunoglobulin receptor KIR2DL3 and its HLA-C1 allotype ligands are protective against chronic HCV infection. A number of studies have shown increased expression of another inhibitory natural killer (NK) cell receptor, CD94:NKG2A, in chronic HCV infection. The ligand for this receptor, HLA-E, usually binds to leader peptides derived from other HLA class I molecules. Up-regulation of HLA-E with concomitant inhibition of NK cells has been thought to be induced by peptides derived from several viruses including one derived from HCV (HCV core35–44) which thus represents a mechanism of immune escape.
Method To determine the effects of viral peptides on NK cell inhibition, we pulsed the TAP-deficient 721.174 cell line with host and virus derived peptides and used these as target cells in flow cytometry assays of NK cell degranulation (measured by CD107a expression).
Results In functional experiments HCV core35–44 inhibited degranulation of the total NK cell population. Unexpectedly, this was due to inhibition of KIR2DL2/3-positive NK cells (one way ANOVA p<0.0001), but not NKG2A-positive NK cells (p=0.94). However, HCV core35–44 peptide increased cell surface expression of both HLA-C and HLA-E. To rationalise this with the previous findings we performed peptide mix experiments using the natural peptide ligands for HLA-E. Such peptides, derived from the leader sequence of host HLA class I molecules, efficiently inhibited NKG2A-positive NK cells. In the presence of a low concentration of a host HLA class I leader sequence peptide, HCV core35–44 had a synergistic effect in suppressing NK cell activity (p<0.0001). A synergistic effect at CD94:NKG2A was also demonstrable for peptides derived from EBV and HIV viruses, which in isolation did not inhibit NK cells, implying that this is a general mechanism for NK cell inhibition.
Conclusion HCV core35–44 inhibits NK cell activity via two distinct mechanisms, directly via KIR2DL2/3, and synergistically via the CD94:NKG2A receptor. This synergistic interaction at CD94:NKG2A represents a novel mechanism for inhibiting NK cells. It demonstrates the sensitivity of NK cells to small changes in the peptide content of HLA class I, and is thus potentially a sensitive mechanism for viral escape from the host innate immune response.
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