Peptide Sharing Between CMV and Mismatched HLA Class I Peptides Promotes Early T-Cell-Mediated Rejection After Kidney Transplantation

Cytomegalovirus (CMV) infection is related to acute rejection and graft loss after kidney transplantation, though the underlying mechanism remains largely unknown. Some CMV strains produce a peptide that is identical to a peptide sequence found in the leader peptide of specific HLA-A and -C alleles. In this retrospective study of 351 kidney transplantations, we explored whether CMV-seropositive recipients without the VMAPRTLIL, VMAPRTLLL or VMAPRTLVL HLA class I leader peptide receiving a transplant from a donor with this peptide, faced an increased risk of T-cell-mediated rejection (TCMR) in the first 90 days after transplantation. An independent case–control cohort was used for validation (n = 122). The combination of recipient CMV seropositivity with the VMAPRTLIL peptide mismatch was associated with TCMR with a hazard ratio (HR) of 3.06 (p = 0.001) in a multivariable analysis. Similarly, the VMAPRTLLL peptide mismatch was associated with TCMR revealing a HR of 2.61 (p = 0.008). Transplantations featuring either a VMAPRTLIL or a VMAPRTLLL peptide mismatch had a significantly higher cumulative TCMR incidence (p < 0.0001), with the primary impact observed in the first 2 weeks post-transplantation. The findings could be validated in an independent cohort. Together, our data strongly suggest that CMV-positive recipients without an HLA peptide identical to a CMV peptide yet transplanted with a donor who does possess this peptide, have a significantly increased risk of early TCMR. Considering the prevention of such an leader peptide mismatch in these patients or adjusting immunosuppression protocols accordingly may hold promise in reducing the incidence of early TCMR.