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 ranging from circulating CD14+ monocytes to differentiated macrophages in the kidney, with one trajectory culminating in a pro-inflammatory macrophage expressing CXCL9 and CXCL10 enriched in the allograft during rejection. 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 patients with rejection but also in biopsies upon rejection. In vitro, allogeneic activation resulted in upregulation of LILRB2 in monocytes. Moreover, LILRB2 is able to bind non-self class I HLA in primary human macrophages resulted in overexpression of proinflammatory genes, suggesting the involvement of this receptor in monocyte/macrophage-associated rejection phenomena.

The authors have declared no competing interest.

NCT02843867

TV is supported by a PhD Fellowship grant from the Research Foundation Flanders (F.W.O.) (grant no. 1S93918N). MN is supported by the Research Foundation Flanders (F.W.O.) as senior clinical investigator (grant agreement no. 1844019N). BL is supported by the Agence Nationale de la Recherche (grant JCJC no. ANR-22-CE18-0011-01). CT is supported by the Agence de la Biomédecine (Recherche et Greffe 2024) and the Bourgogne Franche-Comté region (grant RECH-ANER Initials).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Samples were collected with the regulatory approval of the French Ministry of Health (agreement number DC-2008-713 dated June 11, 2009), and the study was approved by the ethics committee of the Université de Franche-Comté in 2008

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All omic data are already publicly available. All data produced in the present study are available upon reasonable request to the authors