Early intrahepatic antigen-specific retention of naïve CD8<sup>+</sup>T cells is predominantly ICAM-1/LFA-1 dependent in mice

Bertolino, Patrick; Schrage, Arnhild; Bowen, David G.; Klugewitz, Katja; Ghani, Saeed; Eulenburg, Katharina; Holz, Lauren E.; Hogg, Nancy; McCaughan, Geoffrey W.; Hamann, Alf

doi:10.1002/hep.20885

Cited by 52 publications

(56 citation statements)

References 44 publications

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“…5A), a result consistent with flow cytometric and radiolabeling studies 6,27 ; V. Benseler and P. Bertolino unpublished result). Most of the donor T lymphocytes (93%) were found in the sinusoids rather than in portal tracts (Fig.…”

Section: Ihl Interact With Hepatocytes Through Fenestrations In Lsecssupporting

confidence: 83%

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

et al. 2006

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The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node-activated T cells, liver-activated T cells are shortlived, a mechanism that might contribute to the "liver tolerance effect." Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8 ؉ T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that naïve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating naïve CD8 ؉ T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion, this study has identified, at the ultrastructural level, a unique type of interaction between naïve T lymphocytes and liver parenchymal cells in vivo. These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.

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Section: Ihl Interact With Hepatocytes Through Fenestrations In Lsecssupporting

confidence: 83%

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

et al. 2006

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“…Analogous to our study, mice infected with LM (38), EBV, cytomegalovirus (70), and hepatitis A virus (15) showed enrichment of Ag-specific T cells within the liver CD8 ϩ T cell population. Selective retention of activated CD8 ϩ T cells in the liver has been attributed to trapping mediated primarily by ICAM-1 constitutively expressed on sinusoidal endothelium and Kupffer cells (13,71). In the present analysis, the liver, lung, and BAL CD8 ϩ populations showed similar proportions of influenza-specific T cells.…”

Section: Discussionsupporting

confidence: 57%

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Keating

Yue

Rutigliano

et al. 2007

The Journal of Immunology

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Influenza A virus infection of C57BL/6 mice is a well-characterized model for studying CD8+ T cell-mediated immunity. Analysis of primary and secondary responses showed that the liver is highly enriched for CD8+ T cells specific for the immunodominant H2DbNP366–374 (DbNP366) epitope. Functional analysis established that these liver-derived virus-specific CD8+ T cells are fully competent cytotoxic effectors and IFN-γ secretors. In addition, flow cytometric analysis of early apoptotic cells showed that these influenza-specific CD8+ T cells from liver are as viable as those in the spleen, bronchoalveolar lavage, mediastinal lymph nodes, or lung. Moreover, cytokine profiles of the influenza-specific CD8+ T cells recovered from different sites were consistent with the bronchoalveolar lavage, rather than liver population, being the most susceptible to activation-induced cell death. Importantly, adoptively transferred influenza virus-specific CD8+ T cells from the liver survived and were readily recalled after virus challenge. Together, these results show clearly that the liver is not a “graveyard” for influenza virus-specific CD8+ T cells.

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“…3), which is in contrast to intrahepatic T-cell retention in response to ubiquitously presented antigen. 10 However, the contribution of chemokines to antigen-specific CD8 T-cell retention in the liver still remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have investigated CD8 T-cell tolerance toward circulating antigens. However, these studies used minimal MHCbinding peptides 2 or endogenous antigens, 10,11 and thus failed to consider that exogenous circulating protein antigens require cross-presentation for recognition by CD8 T-cells. We have previously reported that LSECs upon adoptive transfer can cross-present antigen to naïve CD8 T-cells initiating T-cell tolerance rather than immunity.…”

mentioning

confidence: 99%

Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization

et al. 2008

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Peripheral CD8 T-cell tolerance can be generated outside lymphatic tissue in the liver, but the course of events leading to tolerogenic interaction of hepatic cell populations with circulating T-cells remain largely undefined. Here we demonstrate that preferential uptake of systemically circulating antigen by murine liver sinusoidal endothelial cells (LSECs), and not by other antigen-presenting cells in the liver or spleen, leads to cross-presentation on major histocompatibility complex (MHC) I molecules, which causes rapid antigen-specific naïve CD8 T-cell retention in the liver but not in other organs. Using bone-marrow chimeras and a novel transgenic mouse model (Tie2-H-2K b mice) with endothelial cell-specific MHC I expression, we provide evidence that cross-presentation by organ-resident and radiationresistant LSECs in vivo was both essential and sufficient to cause antigen-specific retention of naïve CD8 T-cells under noninflammatory conditions. This was followed by sustained CD8 T-cell proliferation and expansion in vivo, but ultimately led to the development of T-cell tolerance.

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Early intrahepatic antigen-specific retention of naïve CD8⁺T cells is predominantly ICAM-1/LFA-1 dependent in mice

Cited by 52 publications

References 44 publications

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization

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Early intrahepatic antigen-specific retention of naïve CD8+T cells is predominantly ICAM-1/LFA-1 dependent in mice

Cited by 52 publications

References 44 publications

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization

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Early intrahepatic antigen-specific retention of naïve CD8⁺T cells is predominantly ICAM-1/LFA-1 dependent in mice