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

Author:

Frieser David1ORCID,Pignata Aurora1,Khajavi Leila1,Shlesinger Danielle2,Gonzalez-Fierro Carmen1,Nguyen Xuan-Hung1ORCID,Yermanos Alexander234ORCID,Merkler Doron45ORCID,Höftberger Romana6ORCID,Desestret Virginie7ORCID,Mair Katharina M.8ORCID,Bauer Jan8ORCID,Masson Frederick1ORCID,Liblau Roland S.19ORCID

Affiliation:

1. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, 31024 Toulouse, France.

2. Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.

3. Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.

4. Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.

5. Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland.

6. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.

7. National Reference Center for Paraneoplastic Neurological Syndromes, MeLiS-UCBL-CNRS, INSERM, Hôpital Neurologique, Hospices Civils de Lyon, 69500 Lyon, France.

8. Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.

9. Department of Immunology, Toulouse University Hospital, 31300 Toulouse, France.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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