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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 7

TE pathogenicity in skin is triggered by migration to the epidermis and interaction with LCs in situ.

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TE pathogenicity in skin is triggered by migration to the epidermis and ...
(A) Graphs showing mean ± SD epidermal accumulation of MataHari T cells following F→M BMT according to the presence or absence of CD207+ cells in the host (n = 5–9/group). Timing of DT or PBS treatment determined depletion or otherwise of different subsets of host CD207+ populations from the skin (all CD207+ n = 7–8/group, LC only n = 8–9/group, or CD207+ dDC only n = 5–6/group) in male Langerin.DTR or established (male Langerin.DTR→B6 male) bone marrow chimeras used as BMT recipients. ***P ≤ 0.001 by 2-tailed Mann-Whitney U test. (B) Left: Representative images of immunofluorescence staining of epidermal sheets showing unilateral LC (green) depletion achieved through intradermal injection of DT (left ear, top image) or PBS (right ear, bottom image). Scale bars: 50 μm. Right: Graphs show summary data for mean ± SD of LC numbers (top) and epidermal TE numbers (bottom) in each ear at day 7 (n = 10). **P ≤ 0.01 by 2-tailed Wilcoxon’s matched-pairs signed-rank test. (C) Evolution of the TRM phenotype of epidermis-located MataHari T cells in the presence (PBS) or absence (DT) of LCs (left: representative FACS plots of CD69 and CD103 expression over time; right: summary data). *P ≤ 0.05 by 2-tailed Wilcoxon’s rank-sum test. (D) Left: Representative images of H&E staining of skin samples from male Langerin.DTR allo-BMT recipients treated with PBS or DT. Right: Summary data of the histopathologic severity score (lines represent median). **P ≤ 0.01 by Mann-Whitney U test. (E) Survival of F→M BMT recipients according to the presence or absence of LCs (BMT + T cells ± DT, n = 8/group) or BMT no–T cell controls (n = 3). Log-rank Mantel-Cox test. BM, bone marrow; BMT, BM transplantation; dDC, dermal dendritic cell; DT, diphtheria toxin; D+, number of days after BMT; Epi, epidermis; H&E, hematoxylin and eosin; LC, Langerhans cell; TE, effector T cell; TRM, resident memory T cell.

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