Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

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Immune function of the blood-brain barrier: incomplete presentation of protein (auto-)antigens by rat brain microvascular endothelium in vitro.

The Journal of Cell Biology ◽

10.1083/jcb.110.5.1757 ◽

1990 ◽

Vol 110 (5) ◽

pp. 1757-1766 ◽

Cited By ~ 100

Author(s):

W Risau ◽

B Engelhardt ◽

H Wekerle

Keyword(s):

T Cells ◽

Endothelial Cells ◽

T Cell ◽

T Lymphocytes ◽

Rat Brain ◽

Blood Brain Barrier ◽

T Cell Activation ◽

Cell Activation ◽

Ifn Gamma

The endothelial blood-brain barrier (BBB) has a critical role in controlling lymphocyte traffic into the central nervous system (CNS), both in physiological immunosurveillance, and in its pathological aberrations. The intercellular signals that possibly could induce lymphocytes to cross the BBB include immunogenic presentation of protein (auto-)antigens by BBB endothelia to circulating T lymphocytes. This concept has raised much, though controversial, attention. We approached this problem by analyzing in vitro immunospecific interactions between clonal rat T lymphocyte lines with syngeneic, stringently purified endothelial monolayer cultures from adult brain micro-vessels. The rat brain endothelia (RBE) were established from rat brain capillaries using double collagenase digestion, density gradient fractionation and selective cytolysis of contaminating pericytes by anti-Thy 1.1 antibodies and complement. Incubation with interferon-gamma in most of the brain-derived endothelial cells induced Ia-antigens in the cytoplasm and on the cell surface in some of the cells. Before the treatment, the cells were completely Ia-negative. Pericytes were unresponsive to IFN-gamma treatment. When confronted with syngeneic T cell lines specific for protein (auto-)antigens (e.g., ovalbumin and myelin basic protein, MBP), RBE were completely unable to induce antigen-specific proliferation of syngeneic T lymphocytes irrespective of pretreatment with IFN-gamma and of cell density. RBE were inert towards the T cells, and did not suppress T cell activation induced by other "professional" antigen presenting cells (APC) such as thymus-derived dendritic cells or macrophages. IFN-gamma-treated RBE were, however, susceptible to immunospecific T cell killing. They were lysed by MBP-specific T cells in the presence of the specific antigen or Con A. Antigen dependent lysis was restricted by the appropriate (MHC) class II product. We conclude that the interaction of brain endothelial cells with encephalitogenic T lymphocytes may involve recognition of antigen in the molecular context of relevant MHC products, but that this interaction per se is insufficient to initiate the full T cell activation program.

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Liver Sinusoidal Endothelial Cells Contribute to Hepatic Antigen-Presenting Cell Function and Th17 Expansion in Cirrhosis

Cells ◽

10.3390/cells9051227 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1227

Author(s):

Esther Caparrós ◽

Oriol Juanola ◽

Isabel Gómez-Hurtado ◽

Amaya Puig-Kroger ◽

Paula Piñero ◽

...

Keyword(s):

Endothelial Cells ◽

T Cell ◽

Bile Duct ◽

T Cell Activation ◽

Cell Activation ◽

Experimental Models ◽

Cd4 T Cell ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Bacterial Peritonitis

Hepatic immune function is compromised during cirrhosis. This study investigated the immune features of liver sinusoidal endothelial cells (LSECs) in two experimental models of cirrhosis. Dendritic cells, hepatic macrophages, and LSECs were isolated from carbon tetrachloride and bile duct-ligated rats. Gene expression of innate receptors, bacterial internalization, co-stimulatory molecules induction, and CD4+ T cell activation and differentiation were evaluated. Induced bacterial peritonitis and norfloxacin protocols on cirrhotic rats were also carried out. LSECs demonstrated an active immunosurveillance profile, as shown by transcriptional modulation of different scavenger and cell-adhesion genes, and their contribution to bacterial internalization. LSECs significantly increased their expression of CD40 and CD80 and stimulated CD4+ T cell activation marker CD71 in both models. The pro-inflammatory Th17 subset was expanded in CCl4-derived LSECs co-cultures. In the bile duct ligation (BDL) model, CD4+ T cell differentiation only occurred under induced bacterial peritonitis conditions. Differentiated pro-inflammatory Th cells by LSECs in both experimental models were significantly reduced with norfloxacin treatment, whereas Foxp3 tolerogenic Th CD4+ cells were expanded. Conclusion: LSECs’ participation in the innate-adaptive immune progression, their ability to stimulate pro-inflammatory CD4+ T cells expansion during liver damage, and their target role in norfloxacin-induced immunomodulation granted a specific competence to this cell population in cirrhosis.

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Immunologic ignorance of vascular endothelial cells expressing minor histocompatibility antigen

Blood ◽

10.1182/blood-2007-09-114769 ◽

2008 ◽

Vol 111 (9) ◽

pp. 4588-4595 ◽

Cited By ~ 11

Author(s):

Beatrice Bolinger ◽

Philippe Krebs ◽

Yinghua Tian ◽

Daniel Engeler ◽

Elke Scandella ◽

...

Keyword(s):

T Cells ◽

Endothelial Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Histocompatibility Antigen ◽

Target Cells ◽

Minor Histocompatibility Antigen

Abstract Endothelial cells (ECs) presenting minor histocompatibility antigen (mhAg) are major target cells for alloreactive effector CD8+ T cells during chronic transplant rejection and graft-versus-host disease (GVHD). The contribution of ECs to T-cell activation, however, is still a controversial issue. In this study, we have assessed the antigen-presenting capacity of ECs in vivo using a transgenic mouse model with beta-galactosidase (β-gal) expression confined to the vascular endothelium (Tie2-LacZ mice). In a GVHD-like setting with adoptive transfer of β-gal–specific T-cell receptor–transgenic T cells, β-gal expression by ECs was not sufficient to either activate or tolerize CD8+ T cells. Likewise, transplantation of fully vascularized heart or liver grafts from Tie2-LacZ mice into nontransgenic recipients did not suffice to activate β-gal–specific CD8+ T cells, indicating that CD8+ T-cell responses against mhAg cannot be initiated by ECs. Moreover, we could show that spontaneous activation of β-gal–specific CD8+ T cells in Tie2-LacZ mice was exclusively dependent on CD11c+ dendritic cells (DCs), demonstrating that mhAgs presented by ECs remain immunologically ignored unless presentation by DCs is granted.

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Enhanced T-Cell Activation Due to Combined Stimulation by Both Endothelial Cells and Monocytes

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.1989.tb01113.x ◽

1989 ◽

Vol 29 (2) ◽

pp. 165-173 ◽

Cited By ~ 3

Author(s):

J. M. TEITEL ◽

A. SHORE ◽

J. McBARRON ◽

A. SCHIAVONE

Keyword(s):

Endothelial Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation

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Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69

Diabetes ◽

10.2337/db07-0855 ◽

2007 ◽

Vol 57 (2) ◽

pp. 484-493 ◽

Cited By ~ 26

Author(s):

S. Srinivasan ◽

D. T. Bolick ◽

D. Lukashev ◽

C. Lappas ◽

M. Sitkovsky ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Hypoxia Inducible Factor ◽

Cd4 T Cell ◽

Sphingosine 1 Phosphate

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A novel intracellular pool of LFA-1 is critical for asymmetric CD8+ T cell activation and differentiation

The Journal of Cell Biology ◽

10.1083/jcb.201609072 ◽

2017 ◽

Vol 216 (11) ◽

pp. 3817-3829 ◽

Cited By ~ 19

Author(s):

Tara Capece ◽

Brandon L. Walling ◽

Kihong Lim ◽

Kyun-Do Kim ◽

Seyeon Bae ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Lymphocyte Function ◽

Intracellular Pool ◽

Important Regulator ◽

Antigen Presenting ◽

Cell Adhesion Receptor

The integrin lymphocyte function–associated antigen 1 (LFA-1; CD11a/CD18) is a key T cell adhesion receptor that mediates stable interactions with antigen-presenting cell (APC), as well as chemokine-mediated migration. Using our newly generated CD11a-mYFP knock-in mice, we discovered that naive CD8+ T cells reserve a significant intracellular pool of LFA-1 in the uropod during migration. Intracellular LFA-1 quickly translocated to the cell surface with antigenic stimulus. Importantly, the redistribution of intracellular LFA-1 at the contact with APC was maintained during cell division and led to an unequal inheritance of LFA-1 in divided T cells. The daughter CD8+ T cells with disparate LFA-1 expression showed different patterns of migration on ICAM-1, APC interactions, and tissue retention, as well as altered effector functions. In addition, we identified Rab27 as an important regulator of the intracellular LFA-1 translocation. Collectively, our data demonstrate that an intracellular pool of LFA-1 in naive CD8+ T cells plays a key role in T cell activation and differentiation.

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The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity

Journal of Experimental Medicine ◽

10.1084/jem.20161524 ◽

2017 ◽

Vol 214 (5) ◽

pp. 1493-1507 ◽

Cited By ~ 27

Author(s):

Yichuan Xiao ◽

Qiang Zou ◽

Xiaoping Xie ◽

Ting Liu ◽

Haiyan S. Li ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Type I ◽

T Cell Homeostasis ◽

Important Regulator ◽

Priming Activity ◽

Specific Deletion

Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell–priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC-specific function of TBK1 in the maintenance of immune homeostasis and tolerance.

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CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration

Science Immunology ◽

10.1126/sciimmunol.aav1263 ◽

2019 ◽

Vol 4 (33) ◽

pp. eaav1263 ◽

Cited By ~ 12

Author(s):

Yanbao Xiong ◽

Wenji Piao ◽

C. Colin Brinkman ◽

Lushen Li ◽

Joseph M. Kulinski ◽

...

Keyword(s):

Endothelial Cells ◽

T Cell ◽

Layer Structure ◽

Lymphatic Vessels ◽

Cd4 T Cell ◽

Lymphatic Endothelial Cells ◽

T Cell Migration ◽

Junction Molecules ◽

Sphingosine 1 Phosphate ◽

Cell Adhesion Molecule 1

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) regulate migration of lymphocytes out of thymus to blood and lymph nodes (LNs) to efferent lymph, whereas their role in other tissue sites is not known. Here, we investigated the question of how these molecules regulate leukocyte migration from tissues through afferent lymphatics to draining LNs (dLNs). S1P, but not other chemokines, selectively enhanced human and murine CD4 T cell migration across lymphatic endothelial cells (LECs). T cell S1PR1 and S1PR4, and LEC S1PR2, were required for migration across LECs and into lymphatic vessels and dLNs. S1PR1 and S1PR4 differentially regulated T cell motility and vascular cell adhesion molecule–1 (VCAM-1) binding. S1PR2 regulated LEC layer structure, permeability, and expression of the junction molecules VE-cadherin, occludin, and zonulin-1 through the ERK pathway. S1PR2 facilitated T cell transcellular migration through VCAM-1 expression and recruitment of T cells to LEC migration sites. These results demonstrated distinct roles for S1PRs in comodulating T cell and LEC functions in migration and suggest previously unknown levels of regulation of leukocytes and endothelial cells during homeostasis and immunity.

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