Donor monocyte–derived macrophages promote human acute graft-versus-host disease
Laura Jardine, … , A.J. Simpson, Matthew Collin
Laura Jardine, … , A.J. Simpson, Matthew Collin
Published May 26, 2020
Citation Information: J Clin Invest. 2020;130(9):4574-4586. https://doi.org/10.1172/JCI133909.
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Research Article Immunology

Donor monocyte–derived macrophages promote human acute graft-versus-host disease

Abstract

Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.

Authors

Laura Jardine, Urszula Cytlak, Merry Gunawan, Gary Reynolds, Kile Green, Xiao-Nong Wang, Sarah Pagan, Maharani Paramitha, Christopher A. Lamb, Anna K. Long, Erin Hurst, Smeera Nair, Graham H. Jackson, Amy Publicover, Venetia Bigley, Muzlifah Haniffa, A.J. Simpson, Matthew Collin

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Figure 3

CD14+CD11c+ myeloid cells are donor-derived macrophages.

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CD14+CD11c+ myeloid cells are donor-derived macrophages. (A) PCA of immu...
(A) PCA of immune gene expression by CD11c+CD14+ GVHD cells and 6 myeloid subsets from healthy control skin. Myeloid cells were sorted from healthy control skin as described in Figure 1 and are annotated accordingly. (B) Heatmap showing unsupervised clustering of CD11c+CD14+ cells from GVHD skin and myeloid cells derived from healthy control skin. Mean log2 expression for each subset is shown. n = 2 for CD141+; n = 3–6 for all other subsets. (C) Example of FISH showing the XY genotype of GVHD macrophages (CD11c+CD14+) and lymphocytes sorted from a female recipient transplanted with a male donor. A single field viewed at ×10 magnification was concatenated to show 8 representative cells per image. Scale bars: 20 μm. (D) Percentages of donor origin analyzed by XY FISH of macrophages (M) and lymphocytes (L) sorted from lesional GVHD skin compared with CD15+ myeloid cells (CD15) and lymphocytes (CD3) sorted from paired blood samples.