Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

Baptiste Lamarthée, Jasper Callemeyn, Yannick Van Herck, Asier Antoranz, Dany Anglicheau, Patrick Boada, Jan Ulrich Becker, Tim Debyser, Frederik De Smet, Katrien De Vusser, Maëva Eloudzeri, Amelie Franken, Wilfried Gwinner, Priyanka Koshy, Dirk Kuypers, Diether Lambrechts, Pierre Marquet, Virginie Mathias, Marion Rabant, Minnie M. Sarwal, Aleksandar Senev, Tara K. Sigdel, Ben Sprangers, Olivier Thaunat, Claire Tinel, Thomas Van Brussel, Amaryllis Van Craenenbroeck, Elisabet Van Loon, Thibaut Vaulet, Francesca Bosisio and Maarten Naesens ()
Additional contact information
Baptiste Lamarthée: Nephrology and Kidney Transplantation Research Group, KU Leuven
Jasper Callemeyn: Nephrology and Kidney Transplantation Research Group, KU Leuven
Yannick Van Herck: Laboratory for Experimental Oncology, KU Leuven
Asier Antoranz: Translational Cell and Tissue Research, KU Leuven
Dany Anglicheau: Assistance Publique-Hôpitaux de Paris
Patrick Boada: UCSF, 513 Parnassus
Jan Ulrich Becker: University Hospital Cologne
Tim Debyser: Nephrology and Kidney Transplantation Research Group, KU Leuven
Frederik De Smet: Translational Cell and Tissue Research, KU Leuven
Katrien De Vusser: Nephrology and Kidney Transplantation Research Group, KU Leuven
Maëva Eloudzeri: Necker Enfants-Malades Institute
Amelie Franken: VIB Center for Cancer Biology
Wilfried Gwinner: Hannover Medical School
Priyanka Koshy: KU Leuven
Dirk Kuypers: Nephrology and Kidney Transplantation Research Group, KU Leuven
Diether Lambrechts: VIB Center for Cancer Biology
Pierre Marquet: Inserm U1248, Limoges University Hospital
Virginie Mathias: EFS, HLA Laboratory
Marion Rabant: Necker Enfants-Malades Institute
Minnie M. Sarwal: UCSF, 513 Parnassus
Aleksandar Senev: Nephrology and Kidney Transplantation Research Group, KU Leuven
Tara K. Sigdel: UCSF, 513 Parnassus
Ben Sprangers: Nephrology and Kidney Transplantation Research Group, KU Leuven
Olivier Thaunat: CIRI, Ecole Normale Supérieure de Lyon
Claire Tinel: Nephrology and Kidney Transplantation Research Group, KU Leuven
Thomas Van Brussel: VIB Center for Cancer Biology
Amaryllis Van Craenenbroeck: Nephrology and Kidney Transplantation Research Group, KU Leuven
Elisabet Van Loon: Nephrology and Kidney Transplantation Research Group, KU Leuven
Thibaut Vaulet: Nephrology and Kidney Transplantation Research Group, KU Leuven
Francesca Bosisio: Translational Cell and Tissue Research, KU Leuven
Maarten Naesens: Nephrology and Kidney Transplantation Research Group, KU Leuven

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.

Date: 2023
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DOI: 10.1038/s41467-023-39859-7

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