Liver Sinusoidal Endothelial Cell Lectin, LSECtin, Negatively Regulates Hepatic T-Cell Immune Response

Tang, Li; Yang, Juntao; Liu, Wanli; Tang, Xiaoming; Chen, Jie; Zhao, Dianyuan; Wang, Min; Xu, Feng; Yang, Liang; Liu, Biao; Sun, Qi-Hong; Zhang, Lingqiang; He, Fuchu

doi:10.1053/j.gastro.2009.07.051

Cited by 100 publications

(94 citation statements)

References 29 publications

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“…We previously reported that LSECtin inhibited T cell immune responses, including decreased T cell activation and proliferation and the downregulation of T cell-derived cytokines (10,21). Therefore, to understand the mechanism by which LSECtin suppresses the intrahepatic effector functions of CD8 + T cells in a mouse model of adenovirus infection, we compared the T cell proliferation in the liver through in vivo BrdU labeling.…”

Section: /2 Mice Upon Viral Infectionmentioning

confidence: 99%

“…Screening of effective small interfering RNA for silencing mouse LSECtin expression in the liver was described previously (10). mLSECtinshort hairpin RNA (shRNA) were cloned into the pSIREN-DNR-DsRed vector (Clontech).…”

Section: Plasmids For Hydrodynamic Injectionmentioning

confidence: 99%

“…Liver sinusoidal endothelial cell lectin (LSECtin), which is a cell-surface molecule that belongs to the C-type lectin receptor family, is constitutively and specifically expressed in LSECs and Kupffer cells (8)(9)(10). We recently reported that LSECtin suppresses intrahepatic T cell immunity and limits immune-mediated liver injury during Con A-induced experimental acute hepatitis (10).…”

mentioning

confidence: 99%

“…We recently reported that LSECtin suppresses intrahepatic T cell immunity and limits immune-mediated liver injury during Con A-induced experimental acute hepatitis (10). The liver-specific expression profile of LSECtin and its ability to limit hepatic T cell immunity inspired us to investigate whether this molecule regulates antiviral immunity and virus invasiveness in the liver and to determine how its expression is modulated in the context of viral infection.…”

mentioning

confidence: 99%

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Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

Liu

Wang

et al. 2013

The Journal of Immunology

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Liver sinusoidal endothelial cell lectin (LSECtin) was recently reported to suppress intrahepatic T cell immunity and to limit immune-mediated liver injury. However, its role in the outcome and pathogenesis of viral infection has not yet been elucidated. Using a mouse model infected with a hepatotropic adenovirus, we found that the absence of LSECtin led to a higher frequency of intrahepatic effector CTLs. These cells produced higher levels of antiviral cytokines and cytotoxic factors and exhibited an increased expression of the transcription factors T-bet and Runx3. This phenotype observed in the LSECtin-knockout cells mediated a more efficient virus-specific cytotoxity compared with that of wild-type cells. As a consequence, LSECtin deficiency significantly accelerated liver adenovirus clearance. In contrast, LSECtin upregulation in the liver delayed viral clearance; this delayed clearance was accompanied by the downregulation of the antiviral activity of CTLs. We further constructed an immunocompetent mouse model of acute hepatitis B viral infection to demonstrate that LSECtin significantly delayed the clearance of hepatitis B virus from blood and infected hepatocytes by limiting the frequency of hepatitis B virus–specific IFN-γ–producing cells. Consistent with this function, LSECtin was upregulated in the liver of mouse models of viral hepatitis. Taken together, our results suggest that LSECtin may facilitate the reduction of liver inflammation at the cost of delaying virus clearance and that this effect might be hijacked by the virus as an escape mechanism.

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Section: /2 Mice Upon Viral Infectionmentioning

confidence: 99%

Section: Plasmids For Hydrodynamic Injectionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

Liu

Wang

et al. 2013

The Journal of Immunology

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“…For example, Tim-3/galectin-9 (Gal-9) pathway modulation affects tumor growth (25); LSECtin, which belongs to the C-type lectin receptor superfamily, is a type II transmembrane protein that is highly expressed in the liver (26). Our previous studies revealed that LSECtin, when expressed in the liver, acted as a co-inhibitory molecule and limited the ability of T-cell immunity to promote HBV tolerance (27,28). Immunologically, tumors are quite similar to chronic viral infections.…”

Section: Introductionmentioning

confidence: 99%

LSECtin Expressed on Melanoma Cells Promotes Tumor Progression by Inhibiting Antitumor T-cell Responses

et al. 2014

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Therapeutic antibodies that target T-cell co-inhibitory molecules display potent antitumor effects in multiple types of cancer. LSECtin is a cell surface lectin of the DC-SIGN family expressed in dendritic cells that inhibits T-cell responses. LSECtin limits T-cell activity in infectious disease, but it has not been studied in cancer. Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. The tumor-promoting effects of LSECtin were abrogated in Rag1 À/À mice or in response to CD4 þ or CD8 þ T-cell depletion. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumorspecific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the coregulatory molecule LAG-3, the blockade of which restored IFNg secretion that was reduced by melanomaderived expression of LSECtin. Together, our findings reveal that common expression of LSECtin in melanoma cells engenders a mechanism of immune escape, with implications for novel immunotherapeutic combination strategies. Cancer Res; 74(13); 3418-28. Ó2014 AACR.

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Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

et al. 2020

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Carbohydrates play a pivotal role in intercellular communication processes. In particular, glycan antigens are key for sustaining homeostasis, helping leukocytes to distinguish damaged tissues and invading pathogens from healthy tissues. From a structural perspective, this cross-talk is fairly complex, and multiple membrane proteins guide these recognition processes, including lectins and Toll-like receptors. Since the beginning of this century, lectins have become potential targets for therapeutics for controlling and/or avoiding the progression of pathologies derived from an incorrect immune outcome, including infectious processes, cancer, or autoimmune diseases. Therefore, a detailed knowledge of these receptors is mandatory for the development of specific treatments. In this review, we summarize the current knowledge about four key C-type lectins whose importance has been steadily growing in recent years, focusing in particular on how glycan recognition takes place at the molecular level, but also looking at recent progresses in the quest for therapeutics.

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Liver Sinusoidal Endothelial Cell Lectin, LSECtin, Negatively Regulates Hepatic T-Cell Immune Response

Abstract: Our results reveal that LSECtin is a novel regulator of T cells and expose a crucial mechanism for hepatic T-cell immune suppression, perhaps opening up a new approach for treatment of inflammatory diseases in the liver.

Cited by 100 publications

References 29 publications

Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

LSECtin Expressed on Melanoma Cells Promotes Tumor Progression by Inhibiting Antitumor T-cell Responses

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

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