The human cytomegalovirus-specific and UL40-mediated imprint in the natural killer cell repertoire is associated with antibody-mediated rejection in lung transplant recipients

BACKGROUND: CD16+ natural killer (NK-) cells play, together with donor-specific antibodies (DSA) and via antibody-dependent cellular cytotoxicity (ADCC), an important role in the pathogenesis of antibody-mediated rejection (ABMR) in lung-transplant recipients (LTRs). Cytotoxic CD16+NKG2C+ NK cells proliferate in response to human Cytomegalovirus (HCMV) infections via the presentation of HCMV-encoded and highly polymorphic UL40 peptides. In our study, we aimed to clarify whether infections with HCMV-strains carrying different UL40 peptide variants are associated with the shift of the NK cell repertoire and the development of ABMR in LTRs.METHODS: We included 30 DSA+ABMR+, 30 DSA+ABMR- and 90 DSA-ABMR- LTRs. In all patients, 1 episode of high-level HCMV-replication occurred. In all DSA+ABMR+ LTRs, HCMV-rep-lication occurred prior to ABMR diagnosis. The association of HCMV UL40 variants with the expan-sion of CD16+ NK cell subsets and ABMR was assessed in NK cell proliferation and ADCC assays.RESULTS: Our study revealed that the VMAPRTLIL and VMTPRTLVL UL40 variants were significantly overrepresented in DSA+ABMR+ LTRs. Both peptides were associated with a pronounced proliferation of cytotoxic and proinflammatory CD16+NKG2C+ NK cells. The stimulation with both peptides led to a shift of the NK cell repertoire towards CD16+NKG2C+ NK cells, which was associated with strong ADCC responses after stimulation with endothelial cells and plasma from DSA+ABMR+ LTRs.CONCLUSIONS: Distinct UL40 peptide variants of the infecting HCMV-strain are associated with the development of ABMR after lung transplantation, due to a shift towards a highly cytotoxic CD16+NKG2C+ NK cell population. These peptides are thus potential prognostic markers for ABMR. J Heart Lung Transplant 2023;42:305-314 (c) 2022 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)