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

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 interactions of the alloreactive inflammatory infiltrate. Here we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies and generated 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 cytotoxic activity is a central mechanism of NK cell mediated graft injury. To unravel the spatial distribution of immune cells in the allograft, multiplexed immunohistochemistry using 38 markers was applied on 18 independent biopsy slides. In antibody-mediated rejection, FcγRIII+ NK and FcγRIII+ nonclassical monocytes specifically infiltrated the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and indicate several potential therapeutic targets to improve allograft longevity.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Seventh Framework Programme (FP7) of the European Commission, in the HEALTH.2012.1.4-1 theme of innovative approaches to solid organ transplantation (grant agreement no. 305499). Research Foundation Flanders , Belgium, under the frame of ERACoSysMed-2, the ERA-Net for Systems Medicine in clinical research and medical practice (project ROCKET, JTC2_29). JC is supported by a PhD Fellowship grant from the Research Foundation Flanders (1196119N). BL is supported by the MiMedI project funded by BPI France (grant DOS0060162/00) and the European Union through the European Regional Development Fund of the Region Bourgogne Franche-Comte (grant FC0013440).

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

This study was approved by the Ethics Committee of the University Hospitals Leuven (S64904).

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Data Availability

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

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