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

• Published in: Nature communications Vol. 10; no. 1; pp. 5350 - 17
• Main Authors: Koenig, Alice, Chen, Chien-Chia, Marçais, Antoine, Barba, Thomas, Mathias, Virginie, Sicard, Antoine, Rabeyrin, Maud, Racapé, Maud, Duong-Van-Huyen, Jean-Paul, Bruneval, Patrick, Loupy, Alexandre, Dussurgey, Sébastien, Ducreux, Stéphanie, Meas-Yedid, Vannary, Olivo-Marin, Jean-Christophe, Paidassi, Héléna, Guillemain, Romain, Taupin, Jean-Luc, Callemeyn, Jasper, Morelon, Emmanuel, Nicoletti, Antonino, Charreau, Béatrice, Dubois, Valérie, Naesens, Maarten, Walzer, Thierry, Defrance, Thierry, Thaunat, Olivier
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 25.11.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alloantigens; Animals; Antibodies; Antibody response; beta 2-Microglobulin - genetics; beta 2-Microglobulin - immunology; beta 2-Microglobulin - metabolism; Biopsy; Cell activation; Cells, Cultured; Endothelial cells; Endothelial Cells - immunology; Endothelial Cells - pathology; Genetic analysis; Graft rejection; Graft Rejection - immunology; Grafting; Grafts; Heart transplantation; Heart Transplantation - methods; Histocompatibility antigen HLA; Humans; Immunoglobulin-like receptors; Immunology; Inflammation - immunology; K562 Cells; Kidney transplantation; Killer cell immunoglobulin-like receptors; Killer Cells, Natural - immunology; Life Sciences; Mice, Inbred C57BL; Mice, Knockout; Microvasculature; Microvessels - pathology; Natural killer cells; Rapamycin; Receptors; Receptors, KIR - immunology; Rejection; Tissue Donors; TOR protein; Transplantation; Transplantation, Homologous; Transplants; Transplants & implants; β2 Microglobulin
• ISSN: 2041-1723; 2041-1723
• 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.