The inhibitory receptor NKG2A is expressed on T-cells during BKPyVANephropathy

Introduction BKPyV-associated nephropathy (BKPyVAN) is a major complication in kidney transplantation. An exhaustion of BKPyV-specific T-cells but not T-cells against other viruses is observed, suggesting a mechanism specifically mediated by BKPyV-specific CD8 + T lymphocytes (BKPyV-LT-CD8). Methods We analyzed the proliferation and specific functions in response to stimulation with BKPyV or CEF peptides of T-cells from 41 kidney transplants (23 without BKPyV-DNAemia and 18 with presumed BKPyVAN). We performed comparative transcriptomics on peripheral BKPyV-LT-CD8 and EBV-LT-CD8 cells, and kidney biopsy specimens from patients with BKPyVAN and stable transplants (GSE47199 dataset). The factors identified were validated by immunohistochemistry on graft biopsy specimens. Results Levels of the KLRC1 transcript encoding NKG2A were higher in peripheral BKPyV-LT-CD8 than in EBV-LT-CD8 cells. They were also higher in BKPyVAN than in stable kidneys. Immunohistochemistry revealed a higher quantity of NKG2A + cells and of NKG2A + CD8 T-cells in BKPyVAN samples. Furthermore, the NKG2A ligand HLA-E tended to be more abundant in tubular epithelial cells from patients with BKPyVAN than in stable kidneys and located close to NKG2A. Conclusion These findings identify NKG2A as a checkpoint inhibitor associated with impaired BKPyV-LT-CD8 function in presumed BKPyVAN. The NKG2A/HLA-E pathway therefore plays a key role in BKPyVAN.