NK Cells Effectively Mediating Antibody-Mediated Kidney Allograft Rejection Requires a Specific Activation Receptor and Graft Expression of the Ligand

Abstract Acute antibody-mediated rejection (aABMR) is an important cause of clinical kidney graft injury and failure. Transcripts associated with NK cell activation in graft biopsies are diagnostic of aABMR, but mechanisms underlying NK cell activation during ABMR remain poorly understood. In contrast to the long-term (> 60 days) survival of complete MHC-mismatched kidney allografts in wild type C57BL/6 mice, B6.CCR5⁻/⁻ recipients develop high titers of donor-specific antibody (DSA) with allograft rejection between days 18 to 28 post-transplant. This has allowed investigation of mechanisms underlying NK cell activation within kidney allografts during aABMR. DSA titers first became detectable in B6.CCR5⁻/⁻ (H-2b) recipients of A/J (H-2a) kidney allografts at day 8 and peaked on day 15 post-transplant and was accompanied by a parallel increase in mRNA levels of Rae-1e, a ligand for the NK cell activation receptor NKG2D. A/J kidneys in B6.CCR5⁻/⁻NKG2D⁻/⁻ recipients and A/J.Rae-1e⁻/⁻ kidneys in B6.CCR5⁻/⁻ recipients survived >60 days, despite high serum DSA levels. Flow cytometric analysis of allograft infiltrating cells in B6.CCR5⁻/⁻ recipients on day 15 post-transplant revealed inflammatory monocyte and NK cell infiltration and NK cell activation to proliferate and express CD107a, a marker of cytotoxic function. These features of aABMR were absent or markedly reduced by recipient NKG2D- or donor graft Rae-1e-deficiency. These findings suggest that interference with expression of allograft Rae-1e or recipient NK cell NKG2D abrogates aABMR despite persistently high DSA levels and that aABMR requires coordination between infiltrating NK cell and inflammatory monocyte activation within the kidney allograft. Competing Interest Statement The authors have declared no competing interest. Abbreviations - aABMR - acute antibody-mediated rejection - DSA - donor-specific antibody