A recipient-derived macrophages subset induces kidney allograft rejection through CXCL10 secretion and LILRB2 signaling

In solid organ transplantation, monocytes and macrophages play a cross-cutting role in the rejection process, irrespective of the transplanted tissue and the type of rejection. Here, we integrated multiple single-cell assays (>150,000 cells) with a broad spectrum of blood-derived and renal allograft-derived cells. We observed 6 cell trajectories enriched in the allograft during rejection, ranging from circulating CD14+ monocytes to differentiated macrophages in the kidney, with one trajectory culminating in a pro-inflammatory macrophage expressing CXCL9 and CXCL10. LILRB2, a gene encoding an HLA-binding receptor, was closely associated with this trajectory, and was found upregulated in a recirculating classical monocyte contingent in peripheral blood of patients with rejection but also in biopsies upon rejection. In vitro , allogeneic stimuli resulted in upregulation of LILRB2 in monocytes. Moreover, LILRB2 was able to bind non-self class I HLA in primary human macrophages resulting in overexpression of proinflammatory genes, suggesting the involvement of this receptor in monocyte/macrophage-associated rejection phenomena. Altogether, the present study provides further insight into the pro-inflammatory axes of recipient-derived monocytes/macrophages, and suggests LILRB2 as a therapeutic target.