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

被引：22

作者：

Aydin, Sidar ^{[1
]}

Pareja, Javier ^{[1
]}

Schallenberg, Vivianne M. ^{[1
]}

Klopstein, Armelle ^{[1
]}

Gruber, Thomas ^{[2
]}

Page, Nicolas ^{[3
,4
]}

Bouillet, Elisa ^{[1
]}

Blanchard, Nicolas ^{[5
]}

Liblau, Roland ^{[5
]}

Koerbelin, Jakob ^{[6
]}

Schwaninger, Markus ^{[7
]}

Johnson, Aaron J. ^{[8
]}

Schenk, Mirjam ^{[2
]}

Deutsch, Urban ^{[1
]}

Merkler, Doron ^{[3
,4
]}

Engelhardt, Britta ^{[1
]}

机构：

[1] Univ Bern, Theodor Kocher Inst, Bern, Switzerland

[2] Univ Bern, Inst Pathol, Expt Pathol, Bern, Switzerland

[3] Univ Geneva, Div Clin Pathol, Dept Pathol & Immunol, Geneva, Switzerland

[4] Univ Hosp Geneva, Geneva, Switzerland

[5] Univ Toulouse, CNRS, Toulouse Inst Infect & Inflammatory Dis, INSERM,UPS, Toulouse, France

[6] Univ Med Ctr Hamburg Eppendorf, Dept Oncol Hematol & Bone Marrow Transplantat, Hamburg, Germany

[7] Univ Lubeck, Inst Expt & Clin Pharmacol & Toxicol, Ctr Brain Behav & Metab, Lubeck, Germany

[8] Mayo Clin, Mayo Clin Grad Sch Biomed Sci, Coll Med, Rochester, MN USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

瑞士国家科学基金会; 美国国家卫生研究院;

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MHC CLASS-I; MULTIPLE-SCLEROSIS; ENDOTHELIAL ICAM-1; TARGET ANTIGENS; STOP SIGNAL; MICE; MODEL; INDUCTION; MIGRATION;

D O I：

10.1038/s41467-023-38703-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system are early hallmarks of multiple sclerosis. Here, the authors demonstrate that brain endothelial cells cross-present antigen to CD8(+) T cells, thereby preventing their migration and initiating BBB breakdown.

引用

页数：20

共 69 条

[1] Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier [J].