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Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of humoral allograft injury. FCGR3AV176/F176polymorphism influences ADCC activity. Additionally, NK cell FcγRIIc expression, dictated by the Q13/STP13polymorphism, was never investigated in kidney transplantation. To assess the clinical relevance of FCGR2CQ13/STP13polymorphism in conjunction with FCGR3AV176/F176polymorphism, 242 kidney transplant recipients were genotyped. NK cell Fc gamma receptor (FcγR) expression and ADCC activity were assessed. RNA sequencing was performed on kidney allograft biopsies to explore the presence of infiltrating FcγR+ NK cells. The FCGR2CQ13allele was enriched in antibody-mediated rejection patients. FcγRIIc Q13+ NK cells had higher ADCC activity than FcγRIIc Q13– NK cells. In combination with the high-affinity FCGR3AV176allele, Q13+V176+ NK cells were the most functionally potent. Q13+ was associated with worse microvascular inflammation and a higher risk of allograft loss. Among V176– patients, previously described in the literature as lower-risk patients, Q13+V176– showed a lower graft survival than Q13–V176– patients. In antibody-mediated rejection biopsies, FCGR2Ctranscripts were enriched and associated with ADCC-related transcripts. Our results suggest that FCGR2CQ13in addition to FCGR3AV176is a significant risk allele that may enhance NK cell-mediated ADCC and contribute to allograft injury and poor survival.

Immune cell–based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet+Eomes+CD8+T cells and CD16brightnatural killer (NK) cells and an increase in putative tolerogenic CD141+CD163+DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ+(IFN-γ+) CD4+and CD8+T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8+T cells, as well as attenuation of cytolytic TH1 effector genes and pathways among intragraft CD8+T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.

The role of Natural killer (NK) cells during kidney allograft antibody-mediated rejection (ABMR) is increasingly recognized, but an in-depth characterization of mechanisms that contribute to such immune response is still under investigation. Here, we characterized phenotypic, functional, and transcriptomic profiles of peripheral blood circulating and allograft infiltrating CD56dimCD16brightNK cells during anti-HLA donor-specific antibody (DSA)+ ABMR. Cross- sectional analyses performed in 71 kidney transplant recipients identified a unique phenotypic circulating CD56dimCD16brightNK cell cluster expanded in DSA+ ABMR. This cluster co-expressed high levels of the interleukin-21 Receptor (IL-21R); Type-1 transcription factors T-bet and EOMES, CD160 and natural killer group 2D cytotoxic and activating co-stimulatory receptors. CD160+IL-21R+NK cells correlated with elevated plasma IL-21, Ki-67+ICOS+(CD278) IL-21-producing circulating T follicular helper cells, enhanced Type-1 pro-inflammatory cytokines, NK cell cytotoxicity, worse microvascular inflammation and graft loss. Single-cell transcriptomic analysis of circulating NK cells delineated an expanded cluster in DSA+ ABMR characterized by elevated pro-inflammatory/cytotoxic pathways, IL-21/STAT3 signaling, and leukocyte trans-endothelial migration pathways. Infiltration of CD160+IL-21R+NK cells with similar transcriptomic profile was detected in DSA+ ABMR allograft biopsies, potentially contributing to allograft injury. Thus, the IL-21/IL-21R axis, linking adaptive and innate humoral allo-immunity, or NK cells may represent appealing immunotherapy targets in DSA+ ABMR.