Local accumulation and activation of regulatory Foxp3+ CD4 TR cells accompanies the appearance of activated CD8 T cells in the liver

Bochtler, Petra; Riedl, Petra; Gomez, Ivan G.; Schirmbeck, Reinhold; Reimann, Jörg

doi:10.1002/hep.22559

Cited by 10 publications

(4 citation statements)

References 22 publications

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“…We found that Treg accumulate in the liver corresponding to the expansion of CD8 OT-I T cells and to the degree of liver inflammation [ 9 ], confirming data from previous reports [ 32 , 33 ]. The enrichment of Treg in the liver during the course of hepatitis suggests an essential role in regulating liver inflammation.…”

Section: Discussionsupporting

confidence: 89%

“…Treg are required to limit liver damage in mice transduced with a hepatitis B virus genome by adenoviral transfer, but also prolong clearance of transduced hepatocytes [ 31 ]. Intramuscular vaccination with hepatitis B antigen (HBsAg) leads to accumulation of antigen-specific CD8 T cells in the liver followed by infiltration of CD4 + Foxp3 + T cells [ 32 ]. Likewise, accumulation of Treg is observed in livers of mice suffering from chronic hepatitis [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis

et al. 2015

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BackgroundThe role of regulatory CD4 T cells (Treg) in immune-mediated liver disease is still under debate. It remains disputed whether Treg suppress T cell-mediated hepatitis in vivo and whether hepatic regulatory T cells are functional in patients with autoimmune hepatitis.MethodsWe used TF-OVA mice, which express ovalbumin in hepatocytes, to investigate the impact of Treg in a model of autoimmune hepatitis. Treg isolated from inflamed livers of TF-OVA mice were tested for their functionality in vitro. By employing double transgenic TF-OVAxDEREG (DEpletion of REGulatory T cells) mice we analyzed whether Treg-depletion aggravates autoimmune inflammation in the liver in vivo.ResultsCD25+Foxp3+ CD4 T cells accumulated in the liver in the course of CD8 T cell-mediated hepatitis. Treg isolated from inflamed livers were functional to suppress CD8 T-cell proliferation in vitro. Depletion of Treg in TF-OVAxDEREG mice dramatically amplified T cell-mediated hepatitis. Repeated administration of antigen-specific CD8 T cells led to a second wave of inflammation only after depletion of Treg.ConclusionOur data add to the evidence for an important role of Treg in autoimmune hepatitis and show that Treg reduce the severity of T-cell mediated hepatitis in vivo. They constitute a key immune cell population that actively maintains a tolerogenic milieu in the liver and protects the liver against repeated inflammatory challenges.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis

et al. 2015

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“…Specific priming and recall of T-cell immunity as well as potent induction of T-cell tolerance and elimination of activated CD8 T cells are observed in the liver [53]; and different types of Treg have been proposed as one of the mechanisms to control the immune responses in the liver [2]. A recent study in a transgenic mouse model shows that the liver can rapidly mobilize and/or recruit Foxp3+CD4 cells with immunosuppressive activity in response to the intrahepatic appearance of peripherally or locally generated activated CD8 cells [54].…”

Section: Treg In Viral Hepatitismentioning

confidence: 99%

Regulatory T cells and viral liver disease

Alatrakchi

Koziel

2009

Journal of Viral Hepatitis

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Important questions remain on the role of T cells in progression of hepatitis virus-mediated liver pathogenesis: are T cells 'Good or Bad'? How could one maintain a beneficial balance, in which regulatory T-cell (Treg) populations might play an important role? Treg are a heterogeneous population of cells, including the classical CD4+CD25+ subset expressing the transcription factor Foxp3, CD4 T cells secreting IL-10 (Tr1) or TGF-beta (Th3), but also some CD8 T cells, double negative T cells and gammadelta T cells. The role of Treg in viral hepatitis, particularly HBV and HCV, seems to range from suppressing T-cell responses directed against hepatitis viruses to down-regulating the immune responses causing the liver damage. Questions also remain unresolved on which Treg populations are important and how to establish a beneficial balance, mostly due to the difficulties in studying the heterogeneous Treg populations but also due to the problem accessing liver, the principal target of hepatitis viruses. Here, we will review progress to date on understanding Treg populations in regard to viral hepatitis.

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“…Crispe and colleagues however demonstrated that activated T cells within the liver remain functional, expand and secrete IFNγ and potentially mediate effector activities in lymphoid organs [46], [47]. It is currently unknown whether the activated T cells observed in our study are derived from systemically activated T cells that subsequently become trapped in the liver [48] or if these represent intrahepatic-derived T cells [49]. Supporting the latter point, hepatic DC from IL-12-treated mice were capable of inducing strong T cell proliferation in vitro , similar to that seen with splenic DC, on a per cell basis.…”

Section: Discussionmentioning

confidence: 67%

Systemic IL-12 Administration Alters Hepatic Dendritic Cell Stimulation Capabilities

Chan¹,

Back²,

Subleski³

et al. 2012

PLoS ONE

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The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2–3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFNγ expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections.

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Local accumulation and activation of regulatory Foxp3+ CD4 TR cells accompanies the appearance of activated CD8 T cells in the liver

Cited by 10 publications

References 22 publications

The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis

The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis

Regulatory T cells and viral liver disease

Systemic IL-12 Administration Alters Hepatic Dendritic Cell Stimulation Capabilities

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