Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver†

Breous, Ekaterina; Somanathan, Suryanarayan; Vandenberghe, Luk; Wilson, James M.

doi:10.1002/hep.23043

Cited by 207 publications

(192 citation statements)

References 38 publications

(35 reference statements)

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“…Previous studies have shown that Tregs play a critical role in liver tolerance (13,22,23); however, in our study, Foxp3 + Treg numbers did not change in HBV-carrier mice, and CD25 + Treg depletion did not influence HBV persistence (Fig. S3).…”

Section: Resultscontrasting

confidence: 70%

“…The liver induces antigen-specific tolerance by a series of mechanisms, including clonal deletion (similar to central tolerance), as well as induction of Tregs and inhibition of memory T-cell responses, which favor peripheral tolerance (6,22,(27)(28)(29). However, the precise mechanisms underlining liver tolerance are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Cytokine levels released into culture supernatant were measured as previously described (22). IL-10 and TGF-β1 levels in culture supernatants were measured with ELISA kits from R&D Systems.…”

Section: Methodsmentioning

confidence: 99%

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Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

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

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The liver plays a critical role in inducing systemic immune tolerance, for example, during limiting hypersensitivity to food allergy and in rendering acceptance of allotransplant or even hepatotropic pathogens. We investigated the unknown mechanisms of liver tolerance by using an established hepatitis B virus (HBV)-carrier mouse model, and found that these mice exhibited an antigen-specific tolerance toward peripheral HBsAg vaccination, showing unenlarged draining lymph node (DLN), lower number of germinal centers (GC), and inactivation of GC B cells and follicular T helper (Tfh) cells. Both in vivo and in vitro immune responses toward HBsAg were suppressed by mononuclear cells from HBV-carrier mice, which were CD4 + Foxp3 − type 1 regulatory T (Tr1)-like cells producing IL-10. Using recipient Rag1 −/− mice, hepatic Tr1-like cells from day 7 of HBV-persistent mice acquired the ability to inhibit anti-HBV immunity 3 d earlier than splenic Tr1-like cells, implying that hepatic Tr1-like cells were generated before those in spleen. Kupffer cell depletion or IL-10 deficiency led to impairment of Tr1-like cell generation, along with breaking HBV persistence. The purified EGFP + CD4 + T cells (containing Tr1-like cells) from HBV-carrier mice trafficked in higher numbers to DLN in recipient mice after HBsAg vaccination, and subsequently inactivated both Tfh cells and GC B cells via secreting IL-10, resulting in impaired GC formation and anti-HB antibody production. Thus, our results indicate Tr1-like cells migrate from the liver to the DLN and inhibit peripheral anti-HBV immunity by negatively regulating GC B cells and Tfh cells.peripheral tolerance | unresponsive

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Section: Resultscontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

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

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“…KC mediate immunosuppression by production of IL‐10, by expression of the negative co‐stimulator for T cell activation programmed cell death ligand‐1 (PD‐L1) 27 and by preventing cytotoxic lymphocyte responses 28. Those activities translate into induction of KC‐dependent protective immune tolerance in liver 29.…”

Section: Phages Kupffer Cells and Immune Homeostasismentioning

confidence: 99%

Therapeutic potential of phages in autoimmune liver diseases

Górski

Jończyk‐Matysiak

Łusiak-Szelachowska

et al. 2018

Clinical and Experimental Immunology

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SummaryAutoimmune liver disease (ALD) poses a difficult medical challenge, as there is a significant number of patients in whom current therapy offers questionable or no benefit, yet its side effects may be serious, including the development of malignancy. Bacterial viruses (phages) have been recognized increasingly as immunomodulators contributing to immune homeostasis and curbing inflammation. Accumulating data suggest that phages may be useful in immunotherapy of ALD. Phages have been shown to down‐regulate the expression and/or production and activity of factors associated with hepatic injury [reactive oxygen species, Toll‐like receptor (TLR)‐4 activation, nuclear factor kappa B (NF‐κB) activation, proinflammatory and procoagulant activities of platelets] and up‐regulate the expression and/or production of factors demonstrated as playing a protective role [interleukin (IL)‐10, IL‐1 receptor antagonist].

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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.…”

mentioning

confidence: 99%

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

Zhang

Yun

et al. 2011

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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Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver†

Cited by 207 publications

References 38 publications

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Therapeutic potential of phages in autoimmune liver diseases

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

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