A subset of pro-inflammatory CXCL10+ LILRB2+ macrophages derives from recipient monocytes and drives renal allograft rejection

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 myeloid 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 . By analyzing over 850 biopsies using deconvolution, we report that they are absent in pre-transplant allografts, while these CXCL10 + macrophages are the immune cells most associated with inflammation during acute rejection. Furthermore, a survival study of over 500 biopsies indicates that they increase the risk of graft loss independently of other immune cells. CXCL10 + macrophages differentiate from recipient monocytes, and we have identified 6 major genes associated with their differentiation, including LILRB2 . In vitro, mimicking allogenic activation of blood monocytes via the CD47/SIRP-a axis induced overexpression of LILRB2, suggesting that CXCL10 + macrophages are activated by this pathway. Finally, we show that macrophages overexpressing LILRB2 induce the proliferation of autologous T lymphocytes. Altogether, the present study provides further insight into the pro-inflammatory axes of recipient-derived monocytes/macrophages, and suggests LILRB2 as a therapeutic target.