P-glycoprotein regulates trafficking of CD8+ T cells to the brain parenchyma

2014 ◽  
Vol 127 (5) ◽  
pp. 699-711 ◽  
Author(s):  
Gijs Kooij ◽  
Jeffrey Kroon ◽  
Debayon Paul ◽  
Arie Reijerkerk ◽  
Dirk Geerts ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Brain Parenchyma ◽  
P Glycoprotein ◽  
The Brain

scholarly journals Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1714-1730 ◽  
Author(s):  
Nina L Fransen ◽  
Cheng-Chih Hsiao ◽  
Marlijn van der Poel ◽  
Hendrik J Engelenburg ◽  
Kim Verdaasdonk ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
White Matter ◽  
Cd8 T Cells ◽  
White Matter Lesions ◽  
Inflammatory Lesion ◽  
Brain Parenchyma ◽  
Perivascular Space ◽  
Normal Appearing White Matter ◽  
The Brain

Abstract Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases. We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3+, CD4+, and CD8+ T cells in 140 subcortical white matter lesions. The location of CD8+ T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8+ T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-appearing white matter (n = 7), and control white matter (n = 10), by flow cytometry. In normal-appearing white matter, the number of T cells was increased compared to control white matter. In active and mixed active/inactive lesions, the number of T cells was further augmented compared to normal-appearing white matter. Active and mixed active/inactive lesions were enriched for both CD4+ and CD8+ T cells, the latter being more abundant in all lesion types. Perivascular clustering of T cells in the medulla oblongata was only found in cases with a progressive disease course and correlated with a higher percentage of mixed active/inactive lesions and a higher lesion load compared to cases without perivascular clusters in the medulla oblongata. In all white matter samples, CD8+ T cells were located mostly in the perivascular space, whereas in mixed active/inactive lesions, 16.3% of the CD8+ T cells were encountered in the brain parenchyma. CD8+ T cells from mixed active/inactive lesions showed a tissue-resident memory phenotype with expression of CD69, CD103, CD44, CD49a, and PD-1 and absence of S1P1. They upregulated markers for homing (CXCR6), reactivation (Ki-67), and cytotoxicity (GPR56), yet lacked the cytolytic enzyme granzyme B. These data show that in chronic progressive multiple sclerosis cases, inflammatory lesion activity and demyelinated lesion load is associated with an increased number of T cells clustering in the perivascular space. Inflammatory active multiple sclerosis lesions are populated by CD8+ tissue-resident memory T cells, which show signs of reactivation and infiltration of the brain parenchyma.

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 IMMU-28. INDUCTION OF TERTIARY LYMPHOID STRUCTURE-LIKE T-CELL CLUSTERS BY DELIVERY OF A NOVEL GENE COMBINATION INTO AN IMMUNOCOMPETENT MOUSE MODEL OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii110-ii111
Author(s):  
Kira Downey ◽  
Bindu Hegde ◽  
Zinal Chheda ◽  
Jason Zhang ◽  
Hideho Okada
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphatic Drainage ◽  
Lymphoid Follicle ◽  
Brain Parenchyma ◽  
Cell Therapies ◽  
Gene Combination ◽  
Cell Clustering ◽  
The Brain

Abstract The lack of conventional lymphatic drainage to and from the brain parenchyma restricts the capacity of the peripheral immune system to recognize and respond to glioma antigens. In some peripheral solid tumor types and central nervous system autoimmunity, the spontaneous development of tertiary lymphoid structures (TLS) with varying degrees of organization have been observed in human patients and mice following chronic inflammation. In the cancer setting, presence of TLS are generally associated with improved prognosis, especially when they are characterized by intratumoral infiltration of CD8+ T-cells. We aimed to induce the development of TLS in vivo, utilizing our SB28 glioblastoma model which is sparsely infiltrated by lymphocytes. As a proof-of-concept study, we stably transduced SB28 with a combination of several TLS-stimulating factors that we’ve identified and injected these cells into the brain parenchyma of syngeneic C57BL/6J mice. A combination of the chemoattractant and lymphoid follicle-stimulating cytokines LIGHT, CCL21, IL-7, and IL-17 produced substantial infiltration of CD8+CD3+ T-cells into the tumor and nearby parenchyma. However, this combination was also associated with accelerated tumor growth. A modified gene combination including LIGHT, CCL21, and IL-7 promoted CD8+CD3+ T-cell infiltration by flow cytometry, T-cell clustering by immunofluorescence analysis, and inhibited tumor burden compared with the control as measured by bioluminescent imaging. There was also evidence of increased lymphatic vasculature around the margins of T-cell clustering as demonstrated by LYVE-1 staining. Together, these analyses highlight a role for these factors in stimulating the recruitment and clustering of T-cell to the glioblastoma microenvironment in a TLS-like phenomenon. Future studies will evaluate whether the recruitment of other lymphocytes and stromal cells to these TLS-like clusters can promote T-cell memory and persistence. Ultimately, we aim to provide these factors utilizing a gene delivery method that will prove translatable to the clinic and complementary to existing T-cell therapies.

scholarly journals CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

2005 ◽  
Vol 79 (21) ◽  
pp. 13509-13518 ◽  
Author(s):  
Jürgen Hausmann ◽  
Axel Pagenstecher ◽  
Karen Baur ◽  
Kirsten Richter ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Virus ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-γ) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-γ-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-γ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-γ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

scholarly journals CD8 T Cells and STAT1 Signaling Are Essential Codeterminants in Protection from Polyomavirus Encephalopathy

2020 ◽  
Vol 94 (8) ◽  
Author(s):  
Taryn E. Mockus ◽  
Colleen S. Netherby-Winslow ◽  
Hannah M. Atkins ◽  
Matthew D. Lauver ◽  
Ge Jin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Chemotherapeutic Agents ◽  
Immune Defense ◽  
Type I ◽  
Viral Control ◽  
Stat1 Signaling ◽  
The Brain

ABSTRACT JC polyomavirus (JCPyV), a human-specific virus, causes the aggressive brain-demyelinating disease progressive multifocal leukoencephalopathy (PML) in individuals with depressed immune status. The increasing incidence of PML in patients receiving immunotherapeutic and chemotherapeutic agents creates a pressing clinical need to define biomarkers to stratify PML risk and develop anti-JCPyV interventions. Mouse polyomavirus (MuPyV) CNS infection causes encephalopathology and may provide insight into JCPyV-PML pathogenesis. Type I, II, and III interferons (IFNs), which all signal via the STAT1 transcription factor, mediate innate and adaptive immune defense against a variety of viral infections. We previously reported that type I and II IFNs control MuPyV infection in non-central nervous system (CNS) organs, but their relative contributions to MuPyV control in the brain remain unknown. To this end, mice deficient in type I, II, or III IFN receptors or STAT1 were infected intracerebrally with MuPyV. We found that STAT1, but not type I, II, or III IFNs, mediated viral control during acute and persistent MuPyV encephalitis. Mice deficient in STAT1 also developed severe hydrocephalus, blood-brain barrier permeability, and increased brain infiltration by myeloid cells. CD8 T cell deficiency alone did not increase MuPyV infection and pathology in the brain. In the absence of STAT1 signaling, however, depletion of CD8 T cells resulted in lytic infection of the choroid plexus and ependymal lining, marked meningitis, and 100% mortality within 2 weeks postinfection. Collectively, these findings indicate that STAT1 signaling and CD8 T cells cocontribute to controlling MuPyV infection in the brain and CNS injury. IMPORTANCE A comprehensive understanding of JCPyV-induced PML pathogenesis is needed to define determinants that predispose patients to PML, a goal whose urgency is heightened by the lack of anti-JCPyV agents. A handicap to achieving this goal is the lack of a tractable animal model to study PML pathogenesis. Using intracerebral inoculation with MuPyV, we found that MuPyV encephalitis in wild-type mice causes an encephalopathy, which is markedly exacerbated in mice deficient in STAT1, a molecule involved in transducing signals from type I, II, and III IFN receptors. CD8 T cell deficiency compounded the severity of MuPyV neuropathology and resulted in dramatically elevated virus levels in the CNS. These findings demonstrate that STAT1 signaling and CD8 T cells concomitantly act to mitigate MuPyV-encephalopathy and control viral infection.

scholarly journals An antigen-specific pathway for CD8 T cells across the blood-brain barrier

2007 ◽  
Vol 204 (9) ◽  
pp. 2023-2030 ◽  
Author(s):  
Ian Galea ◽  
Martine Bernardes-Silva ◽  
Penny A. Forse ◽  
Nico van Rooijen ◽  
Roland S. Liblau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Blood Brain Barrier ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Cerebral Endothelium ◽  
Cognate Antigen ◽  
The Brain

CD8 T cells are nature's foremost defense in encephalitis and brain tumors. Antigen-specific CD8 T cells need to enter the brain to exert their beneficial effects. On the other hand, traffic of CD8 T cells specific for neural antigen may trigger autoimmune diseases like multiple sclerosis. T cell traffic into the central nervous system is thought to occur when activated T cells cross the blood-brain barrier (BBB) regardless of their antigen specificity, but studies have focused on CD4 T cells. Here, we show that selective traffic of antigen-specific CD8 T cells into the brain occurs in vivo and is dependent on luminal expression of major histocompatibility complex (MHC) class I by cerebral endothelium. After intracerebral antigen injection, using a minimally invasive technique, transgenic CD8 T cells only infiltrated the brain when and where their cognate antigen was present. This was independent of antigen presentation by perivascular macrophages. Marked reduction of antigen-specific CD8 T cell infiltration was observed after intravenous injection of blocking anti–MHC class I antibody. These results expose a hitherto unappreciated route by which CD8 T cells home onto their cognate antigen behind the BBB: luminal MHC class I antigen presentation by cerebral endothelium to circulating CD8 T cells. This has implications for a variety of diseases in which antigen-specific CD8 T cell traffic into the brain is a beneficial or deleterious feature.

scholarly journals Immunological context of brain injury

2021 ◽  
Vol 23 (1) ◽  
pp. 163-168
Author(s):  
N. G. Plekhova ◽  
I. V. Radkov ◽  
S. V. Zinoviev ◽  
V. B. Shumatov
Keyword(s):  
Traumatic Brain Injury ◽  
T Cells ◽  
Brain Injury ◽  
Positive Reaction ◽  
Mild Traumatic Brain Injury ◽  
Brain Parenchyma ◽  
Post Injury ◽  
Blood Leukocytes ◽  
Subsequent Decrease ◽  
The Brain

The parameters of several populations of immune cells (T cell populations, macrophage subpopulations) in peripheral blood and brain were studied in a clinically significant model of mild traumatic brain injury among rats. The population of resident cells of innate immunity of microglia and brain astrocytes with local tissue damage is involved in the implementation of the inflammatory response, it is also shown that in case of trauma, blood leukocytes can overcome the blood-brain barrier and penetrate the brain parenchyma. The methods of flow cytometry and immunofluorescence were used. An increase in the number of monocytes and neutrophils up to 1 day, after a mild traumatic brain injury (TBI) with a subsequent decrease to the end of the observation period was noticed. It was determined, that the number of CD45+ cells, CD3+T cells decreased at 1 days post-injury (dpi), and rose slightly by 14 dpi, the percentage of CD4+T cells continuously declined from 7 to 14 dpi, while the percentage of CD8+T cells increased from 7 to 14 dpi. With mild traumatic brain injury in animals, a significant (3-10 times) decrease in the number of microvessels with a positive reaction to the presence of SMI 71 on the 8th and 14th day after head injury was observed. Intensive staining of SMI 71 microvessels was sometimes observed with an increase in the area of a positive reaction. Thin positive deposits of the reaction product are observed in the brain of healthy animals around the wall of the microvessel. In the damaged brain, CD45high/CD11b+ positive macrophages of the M1 subpopulation appeared in the brain tissue on the 2nd day after TBI and a significant amount was observed on the 8-14th day. In the corpus callosum and ipsilateral region of the striatum, the content of cells expressing CD16/11b+ reached a maximum 8 days after TBI, which correlated with a decrease in the positive response to the presence of endothelial antigen SMI 71. Thus, in the acute period of mild TBI, the presence of neuroimmunopathological processes is determined in the brain, which can subsequently result to the dysregulation of neuroimmune connections.

scholarly journals Uncoupling of virus-induced inflammation and anti-viral immunity in the brain parenchyma

2002 ◽  
Vol 83 (7) ◽  
pp. 1735-1743 ◽  
Author(s):  
P. G. Stevenson ◽  
J. M. Austyn ◽  
S. Hawke
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Mhc Class Ii ◽  
Cell Function ◽  
Brain Parenchyma ◽  
Viral Immunity ◽  
Immune Priming ◽  
Specific Immunity ◽  
Histocompatibility Complex ◽  
The Brain

Non-neuroadapted influenza virus confined to the brain parenchyma does not induce antigen-specific immunity. Nevertheless, infection in this site upregulated major histocompatibility complex (MHC) class I and MHC class II expression and recruited lymphocytes to a perivascular compartment. T cells recovered from the brain had an activated/memory phenotype but did not respond to viral antigens. In contrast, T cells recovered from the brain after infection in a lateral cerebral ventricle, which is immunogenic, showed virus-specific responses. As with infectious virus, influenza virus-infected dendritic cells elicited virus-specific immunity when inoculated into the cerebrospinal fluid but not when inoculated into the brain parenchyma. Thus, inflammation and dendritic cell function were both uncoupled from immune priming in the microenvironment of the brain parenchyma and neither was sufficient to overcome immunological privilege.

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