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

Article Article scientifique Article Tissue-resident CD8+ T cells drive compartmentalized and chronic autoimmune damage against CNS neurons eng 2022-04-13 2022-04-13 author Frieser David 0000-0001-8472-3705 author Pignata Aurora author Khajavi Leila author Shlesinger Danielle author Gonzalez-Fierro Carmen author Nguyen Xuan-Hung 0000-0002-2216-8598 author Yermanos Alexander 0000-0001-6238-0588 943156 author Merkler Doron 0000-0002-0247-2007 735735 author Höftberger Romana 0000-0002-5769-1100 author Desestret Virginie 0000-0001-9643-1558 author Mair Katharina M 0000-0003-3339-0714 author Bauer Jan 0000-0001-5802-8047 824110 author Masson Frederick 0000-0001-9909-2985 author Liblau Roland S 0000-0001-5477-5475 eabl6157 10.1126/scitranslmed.abl6157 35417189 1946-6234 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. Animals Autoimmune Diseases / pathology CD8-Positive T-Lymphocytes Central Nervous System Immunologic Memory Mice Neurons Dewey 616.07 Swiss National Science Foundation Deciphering transcriptional regulators of T cell fate decisions in CNS autoimmunity 201271 CH Projects Swiss National Science Foundation Drivers and signatures of neuronal dysfunction in neuroinflammation 185321 CH Projects European Commission Molecular pathology of anti-viral T cell responses in the central nervous system 865026 PATHOCODE EU H2020 137 Département de pathologie et immunologie 21F false 565 La Sclérose en plaques 908 Science translational medicine 14 640 8dd9cf35-8099-4937-b3c1-db7ca893c871 Article (Published version) Restricted scitranslmed.abl6157.pdf 2368094 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Tissue-resident CD8+ T cells drive compartmentalized and chronic autoimmune damage against CNS neurons	Science translational medicine			2022	167	0

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Bauer, Jan