Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

Diehl, Linda; Schurich, Anna; Grochtmann, Regina; Hegenbarth, Silke; Chen, Lieping; Knolle, Percy A.

doi:10.1002/hep.21965

Cited by 246 publications

(230 citation statements)

References 46 publications

(61 reference statements)

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“…Possible mechanisms include: (1) ManR trapping of tumor-derived antigens and other soluble ligands from the blood, to which LSL would normally respond; (2) activation of ManR-dependent signaling pathways promoting LSEC production of immunosuppressors; and (3) decrease of costimulatory molecules and/or increase of coinhibitory molecules. 39 Furthermore, the role of type II suppressive-expressing ManR macrophages, which are also important players of antitumor activity, is not clear. Whatever the mechanism is, our results suggest the contribution of ManR to the regional LSL inhibition occurring in the prometastatic microenvironment generated by tumor-induced hepatic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] Furthermore, ManR is involved in antigen uptake, processing, and presentation to T cells by LSECs, 12 and it has been suggested that this process diminishes local immune response of the liver. 13 However, it is not known how ManR is regulated during the hepatic microvascular infiltration of cancer cells. Furthermore, the contribution of ManR to antitumor defense mechanisms during hepatic metastasis is also unknown.…”

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confidence: 99%

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Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice

et al. 2010

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Mannose receptor (ManR)-mediated liver sinusoidal endothelial cell (LSEC) endocytosis plays a role in antigen presentation and innate immunity, but its role in hepatic metastasis is unknown. We studied ManR-mediated endocytosis during C26 colorectal cancer cell interaction with LSECs and its implications in metastasis. Uptake of labeled ManR ligands (mannan and ovalbumin) and immunohistochemistry were used to study ManR endocytosis and expression. Several interleukin (IL)-1 inhibitors and the cyclooxygenase-2 (COX-2) inhibitor celecoxib were used to analyze the role of IL-1 and COX-2 in ManR regulation. Anti-mouse ManR antibodies and ManR knockout (ManR 2/2 ) mice were used to identify ManR-dependent mechanisms during antitumor immune response of liver sinusoidal lymphocytes (LSLs) interacting with tumor-activated LSECs. ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism:(1) Release of COX-2-dependent IL-1-stimulating factors by lymphocyte function-associated antigen-1-expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1. In addition, LSLs that had interacted with tumoractivated LSECs in vivo decreased their antitumor cytotoxicity and interferon (IFN)-gamma secretion while they increased IL-10 release ex vivo. IFN-gamma/IL-10 ratio also decreased in the hepatic blood from tumor-injected mice. Immunosuppressant effects of tumor-activated LSECs on LSLs were abrogated in both LSECs from ManR 2/2 mice and tumor-activated LSECs given antimouse ManR antibodies. Conclusion: ICAM-1-induced tumor COX-2 decreased antitumor activity during hepatic metastasis through IL-1-induced ManR. ManR constituted a common mediator for prometastatic effects of IL-1, COX-2, and ICAM-1. A rise in hepatic IFN-gamma/IL-10 ratio and antitumor cytotoxicity by way of ManR blockade is consistent with the antimetastatic effects of IL-1, COX-2, and ICAM-1 inhibitors. These data support ManR and ManR-stimulating factors as targets for hepatic colorectal metastasis therapy. (HEPATOLOGY 2010;51:2172-2182 Abbreviations: ASMA, alpha-smooth muscle actin; CM, cell-conditioned medium; COX-2, cyclooxygenase-2; CSPG, chondroitin sulfate proteoglycan; ELISA, enzyme-linked immunosorbent assay; FITC-OVA, fluorescein isothiocyanate-labeled ovalbumin; FSA, formaldehyde treated serum albumin; ICAM-1, intercellular adhesion molecule-1; ICE, IL-1-converting enzyme; IgG2a, immunoglobulin G2a; IL, interleukin; IL-1RI, IL-1 receptor type I; IL-1Ra, IL-1 receptor antagonist; LFA-1, lymphocyte function-associated antigen 1; LSEC, liver sinusoidal endothelial cell; LSL, liver sinusoidal lymphocyte; ManR, mannose receptor; ManR À/À , ManR knockout; SD, standard deviation; sICAM-1, soluble ICAM-1.From the

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice

et al. 2010

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“…It has been associated with exhausted memory T cells in chronic viral infection (22,23) and with cytotoxic T-cell cross-tolerance (24). PD-1 has two known ligands, PDL-1 (B7-H1, CD274) and PDL-2 (B7-DC, CD273) (25,26), and both of them are sufficient to mediate T-cell suppression (27,28).…”

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confidence: 99%

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Gotot¹,

Gottschalk²,

Leopold³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms by which regulatory T cells (T regs ) suppress autoantibody production are unclear. Here we have addressed this question using transgenic mice expressing model antigens in the kidney. We report that T regs were essential and sufficient to suppress autoreactive B cells in an antigen-specific manner and to prevent them from producing autoantibodies. Most of this suppression was mediated through the inhibitory cell-surface-molecule programmed death-1 (PD-1). Suppression required PD-1 expression on autoreactive B cells and expression of the two PD-1 ligands on T regs . PD-1 ligation inhibited activation of autoreactive B cells, suppressed their proliferation, and induced their apoptosis. Intermediate PD-1 + cells, such as T helper cells, were dispensable for suppression. These findings demonstrate in vivo that T regs use PD-1 ligands to directly suppress autoreactive B cells, and they identify a previously undescribed peripheral B-cell tolerance mechanism against tissue autoantigens. Regulatory T cells (T regs ) are powerful suppressors of autoreactive T cells with high therapeutic potential (1-3). T regs also suppress auto-Ab production (4, 5). We recently showed in vivo that they do so in an antigen-specific (Ag-specific) manner (6, 7). These studies used rat insulin promoter HEL/OVA (ROH) mice expressing ovalbumin (OVA) and hen egg lysozyme (HEL) in pancreatic islet β-cells. Autoreactive OVA-and HEL-specific B cells, but not B cells specific for a foreign antigen, failed to proliferate in response to in vivo autoantigen (auto-Ag) challenge and instead underwent apoptosis in a strictly T reg -dependent fashion. T regs can affect B cells indirectly by suppressing the T-helper (Th) cells required for antibody production (8, 9). This did not rule out that T regs might also suppress B cells directly. Cell culture systems have revealed that CD25 + T regs can kill cocultured B cells (10-12). A recent in vivo study showed that T regs enter germinal centers and suppress B cells in this site (13,14). The question whether this occurred directly or indirectly remained open (15). This question is difficult to address in vivo because it requires an experimental system where T regs can suppress B cells but not Th cells.Another open question concerns the molecular mechanisms by which T regs suppress. In principle, T regs may suppress other T cells by (i) secreting inhibitory mediators; (ii) deprivation of survival factors; (iii) killing target cells by granzyme/perforin; and (iv) modulation of DCs by ligating inhibitory T-cell receptors (16,17). The exact contribution of these mechanisms in relevant in vivo situations and the mechanisms by which T regs suppress are unclear.Programmed death-1 (PD-1, CD279) is an activation-induced member of the extended CD28/CTLA-4 family that suppresses T cells (18-21). It has been associated with exhausted memory T cells in chronic viral infection (22,23) and with cytotoxic T-cell cross-tolerance (24). PD-1 has two known ligands, PDL-1 (B7-H1, CD274) and PDL-2 (B7-DC, CD273) (25,...

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“…2 Nonparenchymal liver cells, including liver sinusoidal endothelial cells, dendritic cells (DCs) and Kupffer cells (KCs), have been shown to be responsible for the creation of a local immunosuppressive microenvironment, permitting immune effector cells, such as T cells, to deliver tolerogenic signals, which contributes to the tolerogenic properties of the liver. [3][4][5][6] However, the exact mechanisms for the hepatic immunosuppressive microenvironment remain to be fully understood.…”

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confidence: 99%

Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β

Zhang

Yun

et al. 2010

Hepatology

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The liver, a unique tolerogenic organ, is regarded as the site to trap and destroy aging erythrocytes and activated T cells. However, to date, the mechanisms for why the liver is tolerogenic and whether liver Kupffer cells (KC) are critical phagocytes for apoptotic cells (AC) contributing to the liver immunosuppression remain unclear. Here we report that KC is the main phagocyte for AC in the liver. Contact of AC inhibits proinflammatory cytokine but enhances anti-inflammatory cytokine production of KC in response to lipopolysaccharide (LPS) stimulation. Membrane-bound transforming growth factor (TGF)-b on AC is responsible for the increased production of interleukin (IL)-10 in KC through extracellular signalregulated kinase (ERK) activation via the Smad3 pathway. Importantly, KC-derived IL-10 is critical for AC infusion-mediated protection of endotoxin-induced fulminant hepatitis through suppression of tumor necrosis factor (TNF)-a and nitric oxide (NO) production from KC and consequently attenuation of KC-mediated cytolysis of hepatocytes. Conclusion: AC can be preferentially phagocytosed by KC in the liver, leading to attenuation of fulminant hepatitis through IL-10-mediated suppression of KC-derived inflammatory TNF-a and NO production. These findings demonstrate that priming of KC by AC may contribute to maintain liver immunosuppression, providing a new mechanistic explanation for how immune homeostasis is maintained in the liver. (HEPATOLOGY 2011;53:306-316)

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Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

Cited by 246 publications

References 46 publications

Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice

Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice

Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo

Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β

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