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Peripheral tissues re-program CD8+ T cells for pathogenicity during graftversus- host disease

Santos e Sousa, P; Ciré, S; Conlan, T; Jardine, L; Tkacz, C; Ferrer, IR; Lomas, C; ... Chakraverty, R; + view all (2018) Peripheral tissues re-program CD8+ T cells for pathogenicity during graftversus- host disease. JCI Insight , 3 (5) , Article e97011. 10.1172/jci.insight.97011. Green open access

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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.

Type: Article
Title: Peripheral tissues re-program CD8+ T cells for pathogenicity during graftversus- host disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.97011
Publisher version: http://dx.doi.org/10.1172/jci.insight.97011
Language: English
Additional information: This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http:// creativecommons.org/licenses/ by/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10043271
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