Journal Article

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

Ducreux, Stéphanie, Taupin, Jean-Luc, Walzer, Thierry, Koenig, Alice, Thaunat, Olivier, Nicoletti, Antonino, Olivo-Marin, Jean-Christophe, Sicard, Antoine, Chen, Chien-Chia, Charreau, Béatrice, Mathias, Virginie, Meas-Yedid, Vannary, Paidassi, Héléna, Loupy, Alexandre, Guillemain, Romain, Rabeyrin, Maud, Marçais, Antoine, Dubois, Valérie, Duong-Van-Huyen, Jean-Paul, Bruneval, Patrick, Barba, Thomas, Callemeyn, Jasper, Racapé, Maud, Dussurgey, Sébastien, Morelon, Emmanuel, Defrance, Thierry, Naesens, Maarten

2019

Overview

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. ‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/21 / 13/31 / 13/51 / 13/95 / 14/63 / 631/250/2504 / 631/250/2520 / 64/110 / 64/60 / 692/699/249/2510 / 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 / Humanities and Social Sciences / 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 / multidisciplinary / Natural killer cells / Rapamycin / Receptors / Receptors, KIR - immunology / Rejection / Science / Science (multidisciplinary) / Tissue Donors / TOR protein / Transplantation / Transplantation, Homologous / Transplants / Transplants & implants / β2 Microglobulin