The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity

Bowen, David; Zen, Monica; Holz, Lauren E.; Davis, Thomas J.; McCaughan, Geoffrey W.; Bertolino, Patrick

doi:10.1172/jci200421593

Cited by 264 publications

(157 citation statements)

References 51 publications

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“…Thus, the presence of very few NP-specific CD8 + T cells in the blood of DTg mice, indicates that reactive CD8 + T cells were retained in the liver and do not recirculate between the liver and lymphoid tissues. These observations are similar to those reported from Tg models using adoptive transfer of HAg-specific self-reactive CD8+ T cells [5]. …”

Section: Discussionsupporting

confidence: 90%

“…Many cell types are involved in liver lesions characteristic of AIH, including antigen-presenting cells (APC), B lymphocytes and both CD4 + and CD8 + T lymphocytes [5]. The presence of autoreactive T cells (CD4 + and CD8 + ) in the liver and auto-antibodies (auto-Ab) production directed against various hepatic antigens, reflects the autoimmune character of the disease [6, 7].…”

Section: Introductionmentioning

confidence: 99%

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Mouse liver-specific CD8+ T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes

Chabot

Fakhfakh

Béland

et al. 2013

Journal of Autoimmunity

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CD8+ T-cell immune response to liver antigens is often functionally diminished or absent. This may occur via deletion of these autoaggressive T cells, through the acquisition of an anergic phenotype, or via active suppression mediated by other cell populations. We generated a double transgenic model in which mice express CD8+ T cells specific for the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) and LCMV-NP as a hepatic neo-autoantigen, to study the immunological response of potentially liver antigen autoagressive CD8+ T cells. Autoreactive transgenic CD8+ T cells were analyzed for functionality and cytotoxic effector status. Despite severe peripheral deletion of liver-specific CD8+ T cells, a fraction of autoreactive NP-specific CD8+ T cells accumulate in liver, resulting in hepatocyte injury and production of autoantibodies in both male and female mice. NP-specific intrahepatic T cells showed capacity to proliferate, produce cytokines and up-regulate activation markers. These data provide in vivo evidence that autoreactive CD8+ T cells are activated in the liver and developed an inflammatory process, but require additional factors to cause severe autoimmune destruction of hepatocytes. Our new model will provide a valuable tool for further exploration of the immunological response involved in inflammatory liver diseases, including autoimmune hepatitis.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Mouse liver-specific CD8+ T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes

Chabot

Fakhfakh

Béland

et al. 2013

Journal of Autoimmunity

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“…Hepatocytes prime naïve CD8 + T cell, even when they express low levels of MHC class I molecules 109 . These hepatocyte-primed naive T-cells can expand, but in the absence of co-stimulatory signals they undergo apoptosis, leading to intrahepatic tolerance by clonal deletion 109–111 . Also, when allogeneic hepatocytes are exposed to T-cells, T-cells activate and apoptose 112 .…”

Section: Liver-related Antigen Presenting Cells In Immunity and Tolermentioning

confidence: 99%

Liver Immunology

Bogdanos

Gao

Gershwin

2013

Comprehensive Physiology

181

130

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The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity.

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“…The liver contains distinct populations of APCs including DCs19 75 and other cells capable of antigen presentation such as sinusoidal endothelial cells,76 Kupffer cells,77 78 stellate cells79 and hepatocytes 80. Both the site and nature of the APCs determine the outcome of intrahepatic immune activation 3 54.…”

Section: Immune Activation and Regulation In The Livermentioning

confidence: 99%