TLR-4 Regulates CD8+ T Cell Trapping in the Liver

John, Beena; Crispe, Ian Nicholas

doi:10.4049/jimmunol.175.3.1643

Cited by 50 publications

(49 citation statements)

References 33 publications

(21 reference statements)

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“…In mice, Con A induces a severe liver injury that is a model of human T-cell-mediated hepatitis, which is dependent on the activation of CD4 þ lymphocytes (3) and requires Th1 cytokines such as IL-2, IFN-g, and TNF-a. It is reported that deficiency of Toll signaling resulted in failure to generate Th1-dependent immune responses (16), and TLR4 also plays vital roles in the function of CD4 þ and CD8 þ T cells (17,18). Using antibiotics to reduce the LPS levels and TLR4 knockout mice, we showed that gut-derived LPS can promote Con A-induced liver injury in TLR4-dependent manner.…”

Section: Discussionmentioning

confidence: 85%

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Gut-Derived Lipopolysaccharide Promotes T-Cell–Mediated Hepatitis in Mice through Toll-Like Receptor 4

Yu¹,

Yan²,

Yang³

et al. 2012

Cancer Prevention Research

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Robust clinical and epidemiologic data support the role of inflammation as a key player in hepatocellular carcinoma (HCC) development. Our previous data showed that gut-derived lipopolysaccharide (LPS) promote HCC development by activating Toll-like receptor 4 (TLR4) expressed on myeloid-derived cells. However, the effects of gut-derived LPS on other types of liver injury models are yet to be studied. The purpose of this study was to determine the importance of gut-derived LPS and TLR4 signaling in a T-cellmediated hepatitis-Con A-induced hepatitis model, which mimic the viral hepatitis. Reduction of endotoxin using antibiotics regimen or genetic ablation of TLR4 in mice significantly alleviate Con A-induced liver injury by inhibiting the infiltration of T lymphocytes into the liver and the activation of CD4 þ T lymphocytes as well as the production of T helper 1 cytokines; in contrast, exogenous LPS can promote Con A-induced hepatitis and CD4 þ T cells activation in vivo and in vitro. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored Con A-induced liver injury and inflammation, indicating the major cell target of LPS. In addition, TLR4 may positively regulate the target hepatocellular apoptosis via the perforin/granzyme B pathway. These data suggest that gut-derived LPS and TLR4 play important positive roles in Con A-induced hepatitis and modulation of the gut microbiotia may represent a new avenue for therapeutic intervention to treat acute hepatitis induced by hepatitis virus infection, thus to prevent hepatocellular carcinoma. Cancer Prev Res; 5(9); 1090-102. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 85%

“…TLR4 was also expressed on T lymphocyte, playing a vital role in adaptive immunity. Recent studies have shown the contribution of TLR4 signaling to the trapping of CD8 þ T cells within the murine liver (17).…”

Section: Introductionmentioning

confidence: 99%

Gut-Derived Lipopolysaccharide Promotes T-Cell–Mediated Hepatitis in Mice through Toll-Like Receptor 4

Yu¹,

Yan²,

Yang³

et al. 2012

Cancer Prevention Research

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“…Although there was no overt accumulation of KIR ϩ CD8 ϩ or NKG2A ϩ CD8 ϩ T cells in the patients, our results indicate that within the liver, the frequency of NKG2A ϩ CD8 ϩ T cells, but not KIR ϩ CD8 ϩ T cells, correlates with lesion severity. The increased frequency of NKG2A ϩ CD8 ϩ T cells that we found in liver samples with marked lesion severity could possibly be related to the fact that the liver can retain committed CD8 ϩ T cells, [39][40][41] a phenomenon that could be reinforced during chronic inflammation. In theory, liver NKG2A ϩ CD8 ϩ T cells could contribute to lesions because some of them were perforin ϩ and there were blasting cells with a high forward scatter (FSC high ) (not shown).…”

Section: Discussionmentioning

confidence: 99%

Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C

et al. 2007

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“…The role of liver and spleen in the pathogenesis of various immune-mediated diseases is well known [17,18,30]. Results of a previously published study [30] suggest that the liver is involved in immune modulation by intrahepatic trapping of CD8 + cells and dual function of NK and NKT cells.…”

Section: Discussionmentioning

confidence: 96%

Influence of CD26/dipeptidyl peptidase IV deficiency on immunophenotypic changes during colitis development and resolution

et al. 2016

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A lot of evidence for the importance of CD26/dipeptidyl peptidase IV (CD26/DPP IV) in immunoactivation has been reported; however, its involvement in colitis remains unclear. The aim of this study was to investigate the influence of CD26/DPP IV deficiency on immunophenotypic changes associated with dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) and CD26-deficient mice. Development of clinical symptoms of colitis and animal health status parameters were assessed; the expression of the nuclear factor (NF)-κB p65 subunit was measured by quantitative real-time PCR, while cell characterization was determined by flow cytometry and immunohistochemical staining. DSS treatment induced loss of body weight and colon length shortening in both mouse strains. An increase of myeloperoxidase activity in CD26-deficient mice was more intensive than in WT mice, in spite of similar histopathological changes. Furthermore, a significant increase in the expression of NF-κB p65 subunit in the colon of CD26-deficient mice was determined. The percentage of splenic CD4(+) and CD8(+) cells in the acute phase of colitis was significantly decreased in WT mice, while in the same period, an increase in the percentage of splenic CD8(+) cells was present in CD26-deficient mice. Development of colitis was accompanied by a significant increase in the percentage of intrahepatic NKT cells in both mouse strains, but their percentage in spleen was increased only in CD26-deficient mice. CD26 deficiency was associated with a heightened response to DSS accompanied by increased expression of NF-κB p65 subunit and distinct changes in leukocyte trafficking. These results provide new insights into the role of CD26/DPP IV during the development of colitis.

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TLR-4 Regulates CD8+ T Cell Trapping in the Liver

Cited by 50 publications

References 33 publications

Gut-Derived Lipopolysaccharide Promotes T-Cell–Mediated Hepatitis in Mice through Toll-Like Receptor 4

Gut-Derived Lipopolysaccharide Promotes T-Cell–Mediated Hepatitis in Mice through Toll-Like Receptor 4

Features and distribution of CD8 T cells with human leukocyte antigen class I-specific receptor expression in chronic hepatitis C

Influence of CD26/dipeptidyl peptidase IV deficiency on immunophenotypic changes during colitis development and resolution

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