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

TY - JOUR

T1 - Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization

AU - von Oppen, Nanette

AU - Schurich, Anna

AU - Hegenbarth, Silke

AU - Stabenow, Dirk

AU - Tolba, Rene

AU - Weiskirchen, Ralf

AU - Geerts, Albert

AU - Kolanus, Waldemar

AU - Knolle, Percy

AU - Diehl, Linda

PY - 2009/5

Y1 - 2009/5

N2 - UNLABELLED: 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 radiation-resistant 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.CONCLUSION: Our results show that cross-presentation of circulating antigens by LSECs caused antigen-specific retention of naïve CD8 T-cells and identify antigen-specific T-cell adhesion as the first step in the induction of T-cell tolerance.

AB - UNLABELLED: 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 radiation-resistant 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.CONCLUSION: Our results show that cross-presentation of circulating antigens by LSECs caused antigen-specific retention of naïve CD8 T-cells and identify antigen-specific T-cell adhesion as the first step in the induction of T-cell tolerance.

KW - Animals

KW - Antigen Presentation

KW - Antigens

KW - CD8-Positive T-Lymphocytes

KW - Cell Migration Inhibition

KW - Cells, Cultured

KW - Cross-Priming

KW - Endothelial Cells

KW - Immune Tolerance

KW - Liver

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Ovalbumin

U2 - 10.1002/hep.22795

DO - 10.1002/hep.22795

M3 - SCORING: Journal article

C2 - 19205034

VL - 49

SP - 1664

EP - 1672

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 5

ER -