Faculty Opinions recommendation of The endothelial basement membrane acts as a checkpoint for entry of pathogenic T cells into the brain.

2020 ◽  
Author(s):  
William A Muller
Keyword(s):  
T Cells ◽  
Basement Membrane ◽  
Endothelial Basement Membrane ◽  
The Brain

scholarly journals The endothelial basement membrane acts as a checkpoint for entry of pathogenic T cells into the brain

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Xueli Zhang ◽  
Ying Wang ◽  
Jian Song ◽  
Hanna Gerwien ◽  
Omar Chuquisana ◽  
...  
Keyword(s):  
T Cells ◽  
Basement Membrane ◽  
Immune Cell ◽  
Cell Phenotype ◽  
T Cell Infiltration ◽  
And Migration ◽  
Endothelial Basement Membrane ◽  
Laminin 411

The endothelial cell basement membrane (BM) is a barrier to migrating leukocytes and a rich source of signaling molecules that can influence extravasating cells. Using mice lacking the major endothelial BM components, laminin 411 or 511, in murine experimental autoimmune encephalomyelitis (EAE), we show here that loss of endothelial laminin 511 results in enhanced disease severity due to increased T cell infiltration and altered polarization and pathogenicity of infiltrating T cells. In vitro adhesion and migration assays reveal higher binding to laminin 511 than laminin 411 but faster migration across laminin 411. In vivo and in vitro analyses suggest that integrin α6β1- and αvβ1-mediated binding to laminin 511–high sites not only holds T cells at such sites but also limits their differentiation to pathogenic Th17 cells. This highlights the importance of the interface between the endothelial monolayer and the underlying BM for modulation of immune cell phenotype.

Endothelial basement membrane laminin α5 selectively inhibits T lymphocyte extravasation into the brain

2009 ◽  
Vol 15 (5) ◽  
pp. 519-527 ◽  
Author(s):  
Chuan Wu ◽  
Fredrik Ivars ◽  
Per Anderson ◽  
Rupert Hallmann ◽  
Dietmar Vestweber ◽  
...  
Keyword(s):  
Basement Membrane ◽  
T Lymphocyte ◽  
Endothelial Basement Membrane ◽  
The Brain

Endotoxin Alteration of the Mucopolysaccharide Blood Vessel Coating in Rats

1974 ◽  
Vol 32 ◽  
pp. 148-149
Author(s):  
D. E. Philpott ◽  
A. Takahashi
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cells ◽  
Salivary Gland ◽  
Carotid Artery ◽  
Basement Membrane ◽  
Coronary Vessels ◽  
Ruthenium Red ◽  
E Coli ◽  
Old Rats ◽  
The Brain

Two month, eight month and two year old rats were treated with 10 or 20 mg/kg of E. Coli endotoxin I. P. The eight month old rats proved most resistant to the endotoxin. During fixation the aorta, carotid artery, basil arartery of the brain, coronary vessels of the heart, inner surfaces of the heart chambers, heart and skeletal muscle, lung, liver, kidney, spleen, brain, retina, trachae, intestine, salivary gland, adrenal gland and gingiva were treated with ruthenium red or alcian blue to preserve the mucopolysaccharide (MPS) coating. Five, 8 and 24 hrs of endotoxin treatment produced increasingly marked capillary damage, disappearance of the MPS coating, edema, destruction of endothelial cells and damage to the basement membrane in the liver, kidney and lung.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002181
Author(s):  
Erin F Simonds ◽  
Edbert D Lu ◽  
Oscar Badillo ◽  
Shokoufeh Karimi ◽  
Eric V Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Prolonged Survival ◽  
Tumor Associated Macrophages ◽  
The Brain ◽  
Immune Profiling

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

scholarly journals Epiligrin, a component of epithelial basement membranes, is an adhesive ligand for alpha 3 beta 1 positive T lymphocytes.

1993 ◽  
Vol 121 (5) ◽  
pp. 1141-1152 ◽  
Author(s):  
E A Wayner ◽  
S G Gil ◽  
G F Murphy ◽  
M S Wilke ◽  
W G Carter
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Basement Membrane ◽  
B Cell ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Lymphokine Activated Killer Cells ◽  
Cutaneous Inflammation ◽  
Epidermal Basement Membrane

The cutaneous T cell lymphomas (CTCL), typified by mycosis fungoides, and several chronic T cell mediated dermatoses are characterized by the migration of T lymphocytes into the epidermis (epidermotropism). Alternatively, other types of cutaneous inflammation (malignant cutaneous B cell lymphoma, CBCL, or lymphocytoma cutis, non-malignant T or B cell type) do not show evidence of epidermotropism. This suggests that certain T lymphocyte subpopulations are able to interact with and penetrate the epidermal basement membrane. We show here that T lymphocytes derived from patients with CTCL (HUT 78 or HUT 102 cells), adhere to the detergent-insoluble extracellular matrix prepared from cultured basal keratinocytes (HFK ECM). HUT cell adhesion to HFK ECM was inhibitable with monoclonal antibodies (mAbs) directed to the alpha 3 (P1B5) or beta 1 (P4C10) integrin receptors, and could be up-regulated by an activating anti-beta 1 mAb (P4G11). An inhibitory mAb, P3H9-2, raised against keratinocytes identified epiligrin as the ligand for alpha 3 beta 1 positive T cells in HFK ECM. Interestingly, two lymphocyte populations could be clearly distinguished relative to expression of alpha 3 beta 1 by flow cytometry analysis. Lymphokine activated killer cells, alloreactive cytotoxic T cells and T cells derived from patients with CTCL expressed high levels of alpha 3 beta 1 (alpha 3 beta 1high). Non-adherent peripheral blood mononuclear cells, acute T or B lymphocytic leukemias, or non-cutaneous T or B lymphocyte cell lines expressed low levels of alpha 3 beta 1 (alpha 3 beta 1low). Resting PBL or alpha 3 beta 1low T or B cell lines did not adhere to HFK ECM or purified epiligrin. However, adhesion to epiligrin could be up-regulated by mAbs which activate the beta 1 subunit indicating that alpha 3 beta 1 activity is a function of expression and affinity. In skin derived from patients with graft-vs.-host (GVH) disease, experimentally induced delayed hypersensitivity reactions, and CTCL, the infiltrating T cells could be stained with mAbs to alpha 3 or beta 1 and were localized in close proximity to the epiligrin-containing basement membrane. Infiltrating lymphocytes in malignant cutaneous B disease (CBCL) did not express alpha 3 beta 1 by immunohistochemical techniques and did not associate with the epidermal basement membrane. The present findings clearly define a function for alpha 3 beta 1 in T cells and strongly suggest that alpha 3 beta 1 interaction with epiligrin may be involved in the pathogenesis of cutaneous inflammation.

Chemokine-induced trafficking of T cells into the meninges through the brain "gates"

2014 ◽  
Vol 275 (1-2) ◽  
pp. 202
Author(s):  
Antoine Louveau ◽  
Sachin Gadani ◽  
Tajie Harris ◽  
Jonathan Kipnis
Keyword(s):  
T Cells ◽  
The Brain
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