Abstract
Abstract BACKGROUND Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of the major complications after T-cell depleted HCT. Recovering within weeks after HCT, natural killer (NK) cells are deemed important in the immunopathogenesis of EBV complications. Their role however remains elusive. NK cell responses are regulated by a series of activating and inhibitory cell surface receptors, central to which are the Killer Ig-like Receptors (KIR). Here we hypothesized and tested whether diverse NK cell receptor repertoires can titrate NK cell functional responses to EBV and can potentially modify the risk of developing PTLD. METHODS KIR genotypes, centromeric and telomeric motifs and their variants were determined for 356 allo-HCT donors through next generation sequencing of KIR locus. PBMNCs from KIR typed healthy volunteers were co-cultured with EBV-transformed cells and degranulation and IFNγ producing NK cells were enumerated using multi-parameter flow cytometry. Effect of donor KIR profile on PTLD was tested using competing risks regression statistics. Segregation of NK cell response to EBV across various KIR repertoires was tested by Mann-Whitney U statistics RESULTS At least one copy of Donor tA01 motifs was required for a strong protection against PTLD (p=0.0001, SHR=0.17). The number of EBV induced NK cells increased with increasing tA01 motifs. There was no influence of recipients’ KIR repertoire on the risk of developing PTLD. CONCLUSIONS KIR-regulated NK cells have a profound effect on the risk of PTLD. KIR gene profile based identification of HCT recipients at high risk of PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy.
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