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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 8

LCs are required to induce the pathogenic gene cluster M28.

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LCs are required to induce the pathogenic gene cluster M28.
(A) Left: Gr...
(A) Left: Graph of weighted gene coexpression network analysis-defined modules showing P values for correlation to epidermis (x axis) and differential expression according to presence or absence of LCs (y axis). Right: Heatmap showing the relative expression of M28 genes in the LNs, dermis, and epidermis in the presence (PBS) and absence of LCs (DT). (B) Assessment of effector function (left: Ifng gene and IFN-γ protein expression) and (C) survival/apoptosis (right: Bcl2l1 expression and caspase 3 activity) of skin-infiltrating donor CD8+ T cells in the presence (PBS) and absence of LCs (DT), (n = 5–6/group, all graphs showing mean ± SD). **P ≤ 0.01 by Mann-Whitney U test. DE, differential expression; Der, Dermis; DT, diphtheria toxin; Epi, epidermis; LC, Langerhans cell; LN, lymph node; ND, not detected.

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