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Scientific article
English

Tissue-resident CD8+ T cells drive compartmentalized and chronic autoimmune damage against CNS neurons

Published inScience translational medicine, vol. 14, no. 640, eabl6157
Publication date2022-04-13
First online date2022-04-13
Abstract

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (TRM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8+T cells exhibit a TRM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8+T cells behind the blood-brain barrier adopt a characteristic TRMdifferentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8+T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8+T cells. Consistently, a large fraction of autoreactive tissue-resident CD8+T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8+T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4+T cells. Collectively, our results point to tissue-resident CD8+T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.

eng
Keywords
  • Animals
  • Autoimmune Diseases / pathology
  • CD8-Positive T-Lymphocytes
  • Central Nervous System
  • Immunologic Memory
  • Mice
  • Neurons
Citation (ISO format)
FRIESER, David et al. Tissue-resident CD8+ T cells drive compartmentalized and chronic autoimmune damage against CNS neurons. In: Science translational medicine, 2022, vol. 14, n° 640, p. eabl6157. doi: 10.1126/scitranslmed.abl6157
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ISSN of the journal1946-6234
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