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Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease
Pedro Santos e Sousa, … , Clare L. Bennett, Ronjon Chakraverty
Pedro Santos e Sousa, … , Clare L. Bennett, Ronjon Chakraverty
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e97011. https://doi.org/10.1172/jci.insight.97011.
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Research Article Immunology Transplantation

Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease

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Abstract

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ–specific approaches to block immunopathology while avoiding global immune suppression.

Authors

Pedro Santos e Sousa, Séverine Ciré, Thomas Conlan, Laura Jardine, Claire Tkacz, Ivana R. Ferrer, Cara Lomas, Sophie Ward, Heather West, Simone Dertschnig, Sven Blobner, Terry K. Means, Stephen Henderson, Daniel H. Kaplan, Matthew Collin, Vincent Plagnol, Clare L. Bennett, Ronjon Chakraverty

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Figure 1

TE gene expression profiles are functionally and spatially divergent.

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TE gene expression profiles are functionally and spatially divergent.
(A...
(A) Left: Experimental setup of the B6→129 BMT model. Right, top graph: Kaplan-Meier survival curve (log-rank Mantel-Cox test). Right, bottom graph: clinical GVHD score over time (mean ± SD). BM only (n = 6), BM + T cells (n = 16). (B) Heatmap showing SLO- and GVHD target organ–derived TE expression of cytotoxic and cytokine genes known to be important in TE differentiation. (C) MDS plot showing the proximity of the transcriptional profiles of donor-derived CD8+ T cells isolated from different organs. (D) Graph showing the FDR q value (bars) and NES (color code) calculated by GSEA, comparing the top 10 enriched KEGG pathways in allo-BMT SLO (blue) and GVHD TO (red) groups. BCAA, branched-chain amino acid; BM, bone marrow; BMT, BM transplantation; Der, dermis; Epi, epidermis; FDR, false discovery rate; GSEA, gene set enrichment analysis; GVHD, graft-versus-host disease; IEL, intraepithelial lymphocyte; LP, lamina propria; MDS, multidimensional scaling; MLN, mesenteric lymph node; NES, normalized enrichment score; PLN, peripheral lymph node; SI, small intestine; SLO, secondary lymphoid organ; Sk, skin; TE, effector T cell; TO, target organ.

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