Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration

Pinheiro, Melissa A. Lopes; Kamermans, Alwin; García-Vallejo, Juan J.; Hof, Bert van het; Wierts, Laura; O’Toole, Tom; Boeve, Daniël; Verstege, Marleen I.; Pol, Susanne Ma van der; Kooyk, Yvette van; Vries, Helga E. de; Unger, Wendy W. J.

doi:10.7554/elife.13149

Cited by 42 publications

(37 citation statements)

References 33 publications

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“…33 The internalization and presentation of myelin antigens by the brain endothelial cells through MHC class II guide the migration of antigen-specific T cells into the CNS. 34 The findings of this study suggest that IFN-γ-induced MHC molecules, PD-L1, ICAM-1 and VCAM-1, on endothelial cells may also help in the selective transmigration of neuronal antigen-specific effector T cells during inflammation and autoimmunity ( Figure 5). Collectively, all these mechanisms may have a cumulative effect and consequently play a decisive role in increased severity of EAE in IFN-γ − / − or IFN-γR − / − mice.…”

Section: Discussionmentioning

confidence: 75%

“…(viii) IFN‐γ is known to upregulate PD‐1 on effector CD4 + T cells, and PD‐L1 on antigen‐presenting cells during EAE 33 . The internalization and presentation of myelin antigens by the brain endothelial cells through MHC class II guide the migration of antigen‐specific T cells into the CNS 34 . The findings of this study suggest that IFN‐γ‐induced MHC molecules, PD‐L1, ICAM‐1 and VCAM‐1, on endothelial cells may also help in the selective transmigration of neuronal antigen‐specific effector T cells during inflammation and autoimmunity (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

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IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier

et al. 2017

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Transendothelial migration (TEM) of Th1 and Th17 cells across the blood-brain barrier (BBB) has a critical role in the development of experimental autoimmune encephalomyelitis (EAE). How cytokines produced by inflammatory Th1 and Th17 cells damage the endothelial BBB and promote transendothelial migration of immune cells into the central nervous system (CNS) during autoimmunity is not understood. We therefore investigated the effect of various cytokines on brain endothelial cells. Among the various cytokines tested, such as Th1 (IFN-γ, IL-1α, IL-1β, TNF-α, IL-12), Th2 (IL-3, IL-4, IL-6 and IL-13), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23, GM-CSF) and Treg-specific cytokines (IL-10 and TGF-β), IFN-γ predominantly showed increased expression of ICAM-1, VCAM-1, MAdCAM-1, H2-K and I-A molecules on brain endothelial cells. Furthermore, IFN-γ induced transendothelial migration of CD4 T cells from the apical (luminal side) to the basal side (abluminal side) of the endothelial monolayer to chemokine CCL21 in a STAT-1-dependent manner. IFN-γ also favored the transcellular route of TEM of CD4 T cells. Multicolor immunofluorescence and confocal microscopic analysis showed that IFN-γ induced relocalization of ICAM-1, PECAM-1, ZO-1 and VE-cadherin in the endothelial cells, which affected the migration of CD4 T cells. These findings reveal that the IFN-γ produced during inflammation could contribute towards disrupting the BBB and promoting TEM of CD4 T cells. Our findings also indicate that strategies that interfere with the activation of CNS endothelial cells may help in controlling neuroinflammation and autoimmunity.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier

et al. 2017

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“…These contacts induce the effector T cells to produce pro-inflammatory mediators, trigger tissue invasion and promote the formation of inflammatory infiltrates (57). Other reports confirm that T cells become activated in the perivascular space, but not within the vascular lumen, although previous in vitro studies have shown that endothelial cells can present antigen to adherent myelin-specific T cells (107, 109). In a MBP transfer EAE rat model, the comparison of highly immunogenic MBP-specific and modestly immunogenic MOG-specific T cells revealed that regardless of antigen specificity, the two cell types crawled with similar velocities in blood vessels (107).…”

Section: The Dynamics Of T Cell Activation In the Spinal Cord During Eaementioning

confidence: 86%

Live Imaging of Immune Responses in Experimental Models of Multiple Sclerosis

Rossi

Constantin

2016

Front. Immunol.

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Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by multifocal perivascular infiltrates that predominantly comprise lymphocytes and macrophages. During EAE, autoreactive T cells first become active in the secondary lymphoid organs upon contact with antigen-presenting cells (APCs), and then gain access to CNS parenchyma, through a compromised blood–brain barrier, subsequently inducing inflammation and demyelination. Two-photon laser scanning microscopy (TPLSM) is an ideal tool for intravital imaging because of its low phototoxicity, deep tissue penetration, and high resolution. In the last decade, TPLSM has been used to visualize the behavior of T cells and their contact with APCs in the lymph nodes (LNs) and target tissues in several models of autoimmune diseases. The leptomeninges and cerebrospinal fluid represent particularly important points for T cell entry into the CNS and reactivation following contact with local APCs during the preclinical phase of EAE. In this review, we highlight recent findings concerning the pathogenesis of EAE and MS, emphasizing the use of TPLSM to characterize T cell activation in the LNs and CNS, as well as the mechanisms of tolerance induction. Furthermore, we discuss how advanced imaging unveils disease mechanisms and helps to identify novel therapeutic strategies to treat CNS autoimmunity and inflammation.

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“…The endothelium is involved in MS pathology by recruitment of immune cells to the CNS (Yun, Minagar, & Alexander, 2017). Endothelial cells are involved in antigen presentation of CNS components to antigen-specific lymphocytes (Galea et al, 2007;Lopes Pinheiro et al, 2016;Traugott & Raine, 1985). Blocking co-inhibitory molecules PD-L1 or PD-L2 on human endothelial cells facilitates transmigration responses of lymphocytes in vitro (Pittet, Newcombe, Prat, & Arbour, 2011;Rodig et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

Borggrewe

Grit

Dunnen

et al. 2018

Glia

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V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell‐mediated immunity. Expression changes of other NCRs (PD‐1, PD‐L1/L2, CTLA‐4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 Δ/− mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC‐sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.

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Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration

Cited by 42 publications

References 33 publications

IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier

IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier

Live Imaging of Immune Responses in Experimental Models of Multiple Sclerosis

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

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Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration

Cited by 42 publications

References 33 publications

IFN‐γ promotes transendothelial migration of CD4+ T cells across the blood–brain barrier

IFN‐γ promotes transendothelial migration of CD4+ T cells across the blood–brain barrier

Live Imaging of Immune Responses in Experimental Models of Multiple Sclerosis

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

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Product

Resources

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IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier

IFN‐γ promotes transendothelial migration of CD4⁺ T cells across the blood–brain barrier