FCGR2C Q and FCGR3A V alleles jointly associate with worse natural killer cell-mediated antibody-dependent cellular cytotoxicity and microvascular inflammation in kidney allograft antibody-mediated rejection.

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of humoral allograft injury. FCGR3A V/F polymorphism influences ADCC activity. Additionally, NK cell FcγRIIc expression, dictated by the Q/STP polymorphism, was never investigated in kidney transplantation. To assess the clinical relevance of FCGR2C Q/STP polymorphism in conjunction with FCGR3A V/F polymorphism, 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 FCGR2C Q allele was enriched in antibody-mediated rejection patients. FcγRIIc Q+ NK cells had higher ADCC activity than FcγRIIc Q- NK cells. In combination with the high-affinity FCGR3A V allele, Q+V+ NK cells were the most functionally potent. Q+ was associated with worse microvascular inflammation and a higher risk of allograft loss. Among V- patients, previously described in the literature as lower-risk patients, Q+V- showed a lower graft survival than Q-V- patients. In antibody-mediated rejection biopsies, FCGR2C transcripts were enriched and associated with ADCC-related transcripts. Our results suggest that FCGR2C Q in addition to FCGR3A V is a significant risk allele that may enhance NK cell-mediated ADCC and contribute to allograft injury and poor survival.