1. Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease.
- Author
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Santos E Sousa P, Ciré S, Conlan T, Jardine L, Tkacz C, Ferrer IR, Lomas C, Ward S, West H, Dertschnig S, Blobner S, Means TK, Henderson S, Kaplan DH, Collin M, Plagnol V, Bennett CL, and Chakraverty R
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD metabolism, Antigens, Surface genetics, Antigens, Surface metabolism, Bone Marrow Transplantation adverse effects, Cells, Cultured, Cellular Reprogramming genetics, Disease Models, Animal, Female, Gene Expression Regulation immunology, Graft vs Host Disease pathology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Langerhans Cells metabolism, Lectins, C-Type genetics, Lectins, C-Type metabolism, Male, Mannose-Binding Lectins genetics, Mannose-Binding Lectins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Multigene Family genetics, Multigene Family immunology, Primary Cell Culture, Receptors, Notch metabolism, Skin cytology, Skin pathology, T-Lymphocytes, Cytotoxic metabolism, Transplantation Chimera, Transplantation, Homologous adverse effects, Cellular Reprogramming immunology, Graft vs Host Disease immunology, Langerhans Cells immunology, Skin immunology, T-Lymphocytes, Cytotoxic immunology
- 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.
- Published
- 2018
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