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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie

38 Zitate (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.

Originalsprache	Englisch
Aufsatznummer	3106
Zeitschrift	Nature Communications
Jahrgang	14
Ausgabenummer	1
Seiten (von - bis)	3106
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-023-38703-2
Publikationsstatus	Veröffentlicht - 30.05.2023

Fördermittel

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

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

Dokumente

10.1038/s41467-023-38703-2

Weitere Links

Link to publication in Scopus

Zitieren

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. Artikel 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, Jg. 14, Nr. 1, 3106, S. 3106. https://doi.org/10.1038/s41467-023-38703-2

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T1 - Antigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown

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

PY - 2023/5/30

Y1 - 2023/5/30

N2 - 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.

AB - 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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