A Subset of Pro‐inflammatory CXCL10+ LILRB2+ Macrophages Derives From Recipient Monocytes and Drives Renal Allograft Rejection

This study uncovers a recipient‐derived monocyte‐to‐macrophage trajectory that drives inflammation during kidney transplant rejection. Using over 150 000 single‐cell profiles and more than 850 biopsies, the authors identify CXCL10+ macrophages as key predictors of graft loss. They reveal LILRB2 as a regulator of their differentiation and activation, suggesting a promising therapeutic target. ABSTRACT 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. This study uncovers a recipient-derived monocyte-to-macrophage trajectory that drives inflammation during kidney transplant rejection. Using over 150 000 single-cell profiles and more than 850 biopsies, the authors identify CXCL10 + macrophages as key predictors of graft loss. They reveal LILRB2 as a regulator of their differentiation and activation, suggesting a promising therapeutic target. ABSTRACT 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. Advanced Science, EarlyView.