Antigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown

Sidar Aydin; Javier Pareja; Vivianne M. Schallenberg; Armelle Klopstein; Thomas Gruber; Nicolas Page; Elisa Bouillet; Nicolas Blanchard; Roland Liblau; Jakob Körbelin; Markus Schwaninger; Aaron J. Johnson; Mirjam Schenk; Urban Deutsch; Doron Merkler; Britta Engelhardt

doi:10.1038/s41467-023-38703-2

Antigen recognition detains CD8⁺ T cells at the blood-brain barrier and contributes to its breakdown

Sidar Aydin, Javier Pareja, Vivianne M. Schallenberg, Armelle Klopstein, Thomas Gruber, Nicolas Page, Elisa Bouillet, Nicolas Blanchard, Roland Liblau, Jakob Körbelin, Markus Schwaninger, Aaron J. Johnson, Mirjam Schenk, Urban Deutsch, Doron Merkler, Britta Engelhardt^*

^*Corresponding author for this work

Institute of Experimental and Clinical Pharmacology and Toxicology

34 Citations (Scopus)

Abstract

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8⁺ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8⁺ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8⁺ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8⁺ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8⁺ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8⁺ T cell entry into the CNS and triggers CD8⁺ T cell-mediated focal BBB breakdown.

Original language	English
Article number	3106
Journal	Nature Communications
Volume	14
Issue number	1
Pages (from-to)	3106
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-023-38703-2
Publication status	Published - 30.05.2023

Funding

We thank to Dr. Gaby Enzmann her support with the biosafety level 2 work. Additional thanks go to Charaf Benarafa (IVI, Mittelhäusern, Switzerland) for providing the Granzyme B C57BL/6 mice and to Thomas Hünig (Institute of Virology and Immunobiology, Würzburg, Germany) for providing the ODC-OVA C56BL/J mice. This study was funded by grants from Swiss National Science Foundation (grant numbers 31003A_149420 and 310030_189080) to BE, Fondation Pour L’Aide a la Recherche sur la Sclérose en Plaques (ARSEP) to BE and RL, Fondation pour la Recherche Médicale to RL, Swiss National Science Foundation (grant numbers 310030B_201271 and 310030_185321) to DM, European Research Council grant to DM, National Institutes of Health (grant numbers R01 NS103212 and RF1 NS122174) to AAJ. –/–

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

Access to Document

10.1038/s41467-023-38703-2

Cite this

Aydin, S., Pareja, J., Schallenberg, V. M., Klopstein, A., Gruber, T., Page, N., Bouillet, E., Blanchard, N., Liblau, R., Körbelin, J., Schwaninger, M., Johnson, A. J., Schenk, M., Deutsch, U., Merkler, D., & Engelhardt, B. (2023). Antigen recognition detains CD8⁺ T cells at the blood-brain barrier and contributes to its breakdown. Nature Communications, 14(1), 3106. Article 3106. https://doi.org/10.1038/s41467-023-38703-2

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title = "Antigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown",

abstract = "Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8+ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8+ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8+ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8+ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8+ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8+ T cell entry into the CNS and triggers CD8+ T cell-mediated focal BBB breakdown.",

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Aydin, S, Pareja, J, Schallenberg, VM, Klopstein, A, Gruber, T, Page, N, Bouillet, E, Blanchard, N, Liblau, R, Körbelin, J, Schwaninger, M, Johnson, AJ, Schenk, M, Deutsch, U, Merkler, D & Engelhardt, B 2023, 'Antigen recognition detains CD8⁺ T cells at the blood-brain barrier and contributes to its breakdown', Nature Communications, vol. 14, no. 1, 3106, pp. 3106. https://doi.org/10.1038/s41467-023-38703-2

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AU - Aydin, Sidar

AU - Pareja, Javier

AU - Schallenberg, Vivianne M.

AU - Klopstein, Armelle

AU - Gruber, Thomas

AU - Page, Nicolas

AU - Bouillet, Elisa

AU - Blanchard, Nicolas

AU - Liblau, Roland

AU - Körbelin, Jakob

AU - Schwaninger, Markus

AU - Johnson, Aaron J.

AU - Schenk, Mirjam

AU - Deutsch, Urban

AU - Merkler, Doron

AU - Engelhardt, Britta

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