Non-classical HLA-E restricted CMV 15-mer peptides are recognized by adaptive NK cells and induce memory responses

Introduction Human cytomegalovirus (HCMV) reactivation causes complications in immunocompromised patients after hematopoietic stem cell transplantation (HSCT), significantly increasing morbidity and mortality. Adaptive Natural Killer (aNK) cells undergo a persistent reconfiguration response to HCMV reactivation; however, the exact role of aNK memory surveillance remains elusive. Methods We employed mass spectrometry computational prediction approaches identify HLA-E-restricted peptides that can elucidate responses. also used K562 line transfected with HLA-E0*0103 for specific peptide binding blocking assays. Subsequently, NK were cocultured dendritic (DCs) loaded each identified examine conventional (c)NK Results Here, we discovered three unconventional 15-mer (SEVENVSVNVHNPTG, TSGSDSDEELVTTER, DSDEELVTTERKTPR) derived from pp65-protein elicit responses restricted HCMV. displayed towards HMCV-infected HCMV-seropositive individuals when primed by DCs these predicted 9-mer versions. Blocking interaction between HLA-E activation NKG2C receptor but not inhibitory NKG2A abolished recall Interestingly, compared complex leader VMAPRTLIL, complexes formed changed surface electrostatic potential highly negative. Furthermore, do comprise classical HLA-E-restriction motifs. Discussion These findings suggest differential may result cells. then designed six nonameric based on could necessary therapeutic inventions. The results provide novel insights into HLA-E-mediated signaling networks mediate maximize their reactivity.