Tissue-resident memory CD8+ T cells cooperate with CD4+ T cells to drive compartmentalized immunopathology in the CNS

Article Article scientifique Article Tissue-resident memory CD8+ T cells cooperate with CD4+ T cells to drive compartmentalized immunopathology in the CNS eng 2022-04-13 2022-04-13 author Vincenti Ilena 0000-0003-1061-6071 692782 author Page Nicolas 796315 author Steinbach Karin 770386 author Yermanos Alexander 0000-0001-6238-0588 943156 author Lemeille Sylvain 637517 author Nunez Nicolas author Kreutzfeldt Mario 0000-0003-0335-2733 736806 author Klimek Bogna 827153 author Di Liberto Giovanni 0000-0001-6788-0215 848758 author Egervari Kristof Levente 0000-0001-6763-9069 761273 author Piccinno Margot 933426 author Shammas Ghazal 931455 author Mariotte Alexandre 930752 author Fonta Nicolas 779471 author Liaudet Nicolas 0000-0002-0749-5857 862067 author Shlesinger Danielle author Liuzzi Anna Rita author Wagner Ingrid 604950 author Saadi Cynthia 23667 author Stadelmann Christine 0000-0003-1766-5458 author Reddy Sai 0000-0002-9177-0857 author Becher Burkhard 0000-0002-1541-7867 author Merkler Doron 0000-0002-0247-2007 735735 eabl6058 10.1126/scitranslmed.abl6058 35417190 1946-6234 In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8+TRMpersisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8+TRM. Subsequently, CD8+TRMexpanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8+T cells. However, in the absence of CD4+T cells, TCF-1+CD8+TRMfailed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8+T cells expressing TCF-1 that predominantly exhibited a TRM-like phenotype. Together, our study provides evidence for CD8+TRM-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions. Autoantigens CD4-Positive T-Lymphocytes CD8-Positive T-Lymphocytes Central Nervous System Humans Immunologic Memory Inflammation Lymphocytic choriomeningitis virus 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 36365b21-b0b5-4d5d-9ae4-8f8a5702e02a Article (Published version) Restricted Tissue-resident memory.pdf 9003391 application/pdf 52423361-2a55-42ba-a91d-226db8a7b8ae Supplemental data Restricted scitranslmed.abl6058_sm.pdf 2532770 application/pdf 748fe59b-8127-4ec6-907d-f7556e934edf Supplemental data Restricted scitranslmed.abl6058_data_file_s1.xlsx 99743 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet db17697c-1b1d-45ca-b05b-03651a521b39 Supplemental data Restricted Copie de scitranslmed.abl6058_table.xlsx 30409 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 33b98fcc-cfb3-4ccf-86cc-02f386e77568 Supplemental data Restricted scitranslmed.abl6058_movie_s1.mp4 3249453 video/mp4 9f35206e-8b7b-4565-bcec-6b7528bd2e80 Supplemental data Restricted scitranslmed.abl6058_movie_s2.mp4 2915986 video/mp4 restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Tissue-resident memory CD8+ T cells cooperate with CD4+ T cells to drive compartmentalized immunopathology in the CNS	Science translational medicine			2022	232	0

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Saadi, Cynthia