Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants

Nat Commun. 2019 Nov 25;10(1):5350. doi: 10.1038/s41467-019-13113-5.


Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Endothelial Cells / immunology
  • Endothelial Cells / pathology
  • Graft Rejection / immunology*
  • Heart Transplantation / methods*
  • Humans
  • Inflammation / immunology*
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / pathology
  • Receptors, KIR / immunology*
  • Tissue Donors
  • Transplantation, Homologous
  • beta 2-Microglobulin / genetics
  • beta 2-Microglobulin / immunology
  • beta 2-Microglobulin / metabolism


  • Receptors, KIR
  • beta 2-Microglobulin