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 2

CD14+CD11c+ cells are small migratory macrophages with monocyte antigen expression.

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CD14+CD11c+ cells are small migratory macrophages with monocyte antigen ...
(A) May-Grünwald Giemsa–stained cytospins of CD11c+CD14+ and CD11c–CD14+ myeloid cells sorted from GVHD dermis and healthy controls. Representative cells from 2 to 4 concatenated images are shown. Scale bar: 20 μm. (B) Flow cytometry analysis of CD45+HLA-DR+ leukocytes migrating from explanted GVHD or healthy control skin over 48 hours in vitro. Gating as in Figure 1. (C) Comparison of CD14/CD1c ratio in migrating cells from GVHD skin (n = 14) and healthy controls (n = 6). Data are represented as mean ± SEM. ***P = 0.0002, Mann-Whitney U test. (D) Relative expression of selected antigens on CD11c+CD14+ cells migrating from GVHD skin (red line) or healthy control (blue line) compared with isotype control (gray line). Representative data from at least 3 donors are shown.