scholarly journals Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood–brain barrier

2021 ◽  
Vol 134 (8) ◽  
Author(s):  
Mariana Castro Dias ◽  
Adolfo Odriozola Quesada ◽  
Sasha Soldati ◽  
Fabio Bösch ◽  
Isabelle Gruber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Brain Barrier ◽  
Immune Surveillance ◽  
Brain Barrier ◽  
Activated T Cells ◽  
Blood Brain ◽  
Primary Mouse ◽  
Underlying Mechanisms

ABSTRACT The migration of activated T cells across the blood–brain barrier (BBB) is a critical step in central nervous system (CNS) immune surveillance and inflammation. Whereas T cell diapedesis across the intact BBB seems to occur preferentially through the BBB cellular junctions, impaired BBB integrity during neuroinflammation is accompanied by increased transcellular T cell diapedesis. The underlying mechanisms directing T cells to paracellular versus transcellular sites of diapedesis across the BBB remain to be explored. By combining in vitro live-cell imaging of T cell migration across primary mouse brain microvascular endothelial cells (pMBMECs) under physiological flow with serial block-face scanning electron microscopy (SBF-SEM), we have identified BBB tricellular junctions as novel sites for T cell diapedesis across the BBB. Downregulated expression of tricellular junctional proteins or protein-based targeting of their interactions in pMBMEC monolayers correlated with enhanced transcellular T cell diapedesis, and abluminal presence of chemokines increased T cell diapedesis through tricellular junctions. Our observations assign an entirely novel role to BBB tricellular junctions in regulating T cell entry into the CNS. This article has an associated First Person interview with the first author of the paper.

scholarly journals Brain endothelial antigen presentation detains CD8+ T cells at the blood-brain barrier leading to its breakdown

2021 ◽  
Author(s):  
Sidar Aydin ◽  
Javier Pareja ◽  
Vivianne M. Schallenberg ◽  
Armelle Klopstein ◽  
Thomas Gruber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Brain Barrier ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Cell Entry ◽  
Brain Barrier ◽  
Blood Brain ◽  
Primary Mouse

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 was proposed to promote CD8+ T-cell entry into the CNS. Employing live cell imaging and primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB and a mouse model of CNS autoimmunity, we here show that pMBMECs process and present antigens leading to effector CD8+ T-cell differentiation. Under physiological flow, endothelial Ag-presentation prohibited CD8+ T-cell crawling and diapedesis leading to pMBMEC apoptosis. Reduced motility of Ag-specific CD8+ T cells was also observed in CNS microvessels in neuroinflammation in vivo. Luminal MHC class I Ag-presentation at the BBB thus prohibits CD8+ T-cell entry into the CNS and rather triggers CD8+ T cell mediated focal BBB breakdown.

Activated T cells mediate direct blood–brain barrier endothelial cell death and dysfunction

Neuroreport ◽  
2002 ◽  
Vol 13 (18) ◽  
pp. 2587-2591 ◽  
Author(s):  
Kian H. Tan ◽  
Wendy M. Purcell ◽  
Simon J. R. Heales ◽  
Julie D. McLeod ◽  
Roger D. Hurst
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Activated T Cells ◽  
Blood Brain ◽  
Endothelial Cell Death

scholarly journals CCR5 expression on monocytes and T cells: Modulation by transmigration across the blood–brain barrier in vitro

2006 ◽  
Vol 243 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Eroboghene E. Ubogu ◽  
Melissa K. Callahan ◽  
Barbara H. Tucky ◽  
Richard M. Ransohoff
Keyword(s):  
T Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Ccr5 Expression ◽  
Blood Brain

scholarly journals Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 837
Author(s):  
Takashi Fujimoto ◽  
Yoichi Morofuji ◽  
Andrej Kovac ◽  
Michelle A. Erickson ◽  
Mária A. Deli ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Neuroprotective Effects ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells ◽  
Pharmacological Significance ◽  
Primary Mouse

Statins have neuroprotective effects on neurological diseases, including a pleiotropic effect possibly related to blood–brain barrier (BBB) function. In this study, we investigated the effects of pitavastatin (PTV) on lipopolysaccharide (LPS)-induced BBB dysfunction in an in vitro BBB model comprising cocultured primary mouse brain endothelial cells, pericytes, and astrocytes. LPS (1 ng/mL, 24 h) increased the permeability and lowered the transendothelial electrical resistance of the BBB, and the co-administration of PTV prevented these effects. LPS increased the release of interleukin-6, granulocyte colony-stimulating factor, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and regulated on activation, normal T-cell expressed and secreted from the BBB model. PTV inhibited the LPS-induced release of these cytokines. These results suggest that PTV can ameliorate LPS-induced BBB dysfunction, and these effects might be mediated through the inhibition of LPS-induced cytokine production. Clinically, therapeutic approaches using statins combined with novel strategies need to be designed. Our present finding sheds light on the pharmacological significance of statins in the treatment of central nervous system diseases.

scholarly journals Endothelial Cell Laminin Isoforms, Laminins 8 and 10, Play Decisive Roles in T Cell Recruitment across the Blood–Brain Barrier in Experimental Autoimmune Encephalomyelitis

2001 ◽  
Vol 153 (5) ◽  
pp. 933-946 ◽  
Author(s):  
Michael Sixt ◽  
Britta Engelhardt ◽  
Friederike Pausch ◽  
Rupert Hallmann ◽  
Olaf Wendler ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cell ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Blood Brain Barrier ◽  
Basement Membranes ◽  
Brain Barrier ◽  
Autoimmune Encephalomyelitis ◽  
Blood Brain ◽  
Experimental Autoimmune

An active involvement of blood–brain barrier endothelial cell basement membranes in development of inflammatory lesions in the central nervous system (CNS) has not been considered to date. Here we investigated the molecular composition and possible function of the extracellular matrix encountered by extravasating T lymphocytes during experimental autoimmune encephalomyelitis (EAE). Endothelial basement membranes contained laminin 8 (α4β1γ1) and/or 10 (α5β1γ1) and their expression was influenced by proinflammatory cytokines or angiostatic agents. T cells emigrating into the CNS during EAE encountered two biochemically distinct basement membranes, the endothelial (containing laminins 8 and 10) and the parenchymal (containing laminins 1 and 2) basement membranes. However, inflammatory cuffs occurred exclusively around endothelial basement membranes containing laminin 8, whereas in the presence of laminin 10 no infiltration was detectable. In vitro assays using encephalitogenic T cell lines revealed adhesion to laminins 8 and 10, whereas binding to laminins 1 and 2 could not be induced. Downregulation of integrin α6 on cerebral endothelium at sites of T cell infiltration, plus a high turnover of laminin 8 at these sites, suggested two possible roles for laminin 8 in the endothelial basement membrane: one at the level of the endothelial cells resulting in reduced adhesion and, thereby, increased penetrability of the monolayer; and secondly at the level of the T cells providing direct signals to the transmigrating cells.

scholarly journals Postarrest stalling rather than crawling favors CD8 + over CD4 + T‐cell migration across the blood–brain barrier under flow in vitro

2016 ◽  
Vol 46 (9) ◽  
pp. 2187-2203 ◽  
Author(s):  
Henriette Rudolph ◽  
Armelle Klopstein ◽  
Isabelle Gruber ◽  
Claudia Blatti ◽  
Ruth Lyck ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Blood Brain Barrier ◽  
Cd4 T Cell ◽  
Brain Barrier ◽  
T Cell Migration ◽  
Blood Brain

scholarly journals Simvastatin Blocks Blood-Brain Barrier Disruptions Induced by Elevated Cholesterol Both In Vivo and In Vitro

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Xijuan Jiang ◽  
Maojuan Guo ◽  
Jinling Su ◽  
Bin Lu ◽  
Dongming Ma ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cholesterol Content ◽  
Brain Barrier ◽  
Blue Dye ◽  
Simvastatin Therapy ◽  
Blood Brain ◽  
Elevated Cholesterol ◽  
Underlying Mechanisms

Background. Hypercholesterolemia and disruptions of the blood brain barrier (BBB) have been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease (AD). Simvastatin therapy may be of benefit in treating AD; however, its mechanism has not been yet fully understood.Objective. To explore whether simvastatin could block disruption of BBB induced by cholesterol both in vivo and in vitro.Methods. New Zealand rabbits were fed cholesterol-enriched diet with or without simvastatin. Total cholesterol of serum and brain was measured. BBB dysfunction was evaluated. To further test the results in vivo, rat brain microvascular endothelial cells (RBMECs) were stimulated with cholesterol in the presence/absence of simvastatin in vitro. BBB disruption was evaluated.Results. Simvastatin blocked cholesterol-rich diet induced leakage of Evan's blue dye. Cholesterol content in the serum was affected by simvastatin, but not brain cholesterol. Simvastatin blocked high-cholesterol medium-induced decrease in TEER and increase in transendothelial FITC-labeled BSA Passage in RBMECs.Conclusions. The present study firstly shows that simvastatin improves disturbed BBB function both in vivo and in vitro. Our data provide that simvastatin may be useful for attenuating disturbed BBB mediated by hypercholesterolemia.

scholarly journals Human-derived Treg and MSC combination therapy may augment immunosuppressive potency in vitro, but did not improve blood brain barrier integrity in an experimental rat traumatic brain injury model

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251601
Author(s):  
Henry W. Caplan ◽  
Karthik S. Prabhakara ◽  
Naama E. Toledano Furman ◽  
Soheil Zorofchian ◽  
Cecilia Martin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
T Cells ◽  
Brain Injury ◽  
Combination Therapy ◽  
Immune Responses ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

Traumatic brain injury (TBI) causes both physical disruption of the blood brain barrier (BBB) and altered immune responses that can lead to significant secondary brain injury and chronic inflammation within the central nervous system (CNS). Cell therapies, including mesenchymal stromal cells (MSC), have been shown to restore BBB integrity and augment endogenous splenic regulatory T cells (Treg), a subset of CD4+ T cells that function to regulate immune responses and prevent autoimmunity. We have recently shown that infusion of human cord blood-derived Treg decreased neuroinflammation after TBI in vivo and in vitro. However, while both cells have demonstrated anti-inflammatory and regenerative potential, they likely utilize differing, although potentially overlapping, mechanisms. Furthermore, studies investigating these two cell types together, as a combination therapy, are lacking. In this study, we compared the ability of Treg+MSC combination therapy, as well as MSC and Treg monotherapies, to improve BBB permeability in vivo and suppress inflammation in vitro. While Treg+MSC combination did not significantly augment potency in vivo, our in vitro data demonstrates that combination therapy may augment therapeutic potency and immunosuppressive potential compared to Treg or MSC monotherapy.

Sign in / Sign up

Export Citation Format

Share Document