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

Abstract

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.

Podocytes Are Nonhematopoietic Professional Antigen-Presenting Cells

“…So far, crosspresentation capacity has been shown for macrophages and DCs and only a few other hematopoietic (e.g., B cells 25 and neutrophils 26 ) and nonhematopoietic (liver sinusoidal endothelial cells 27 ) cell types. In contrast to liver sinusoidal endothelial cells, which induce a liver-specific T cell tolerization, 28 we found that activated podocytes are potent activators of CD8+ T cells. Next, we showed that this finding could also happen in vivo.…”

Emerging roles of lymphatic endothelium in regulating adaptive immunity

“…However, the ability of non-hematopoietic cells to induce peripheral CD8 + T cell tolerance is not unique to LECs and FRCs. Liver sinusoidal endothelial cells (LSECs) are considered critical for tolerance to food antigens, as they mount CD8 + deletional tolerance against exogenous antigens coming directly from the gut (68,69). Tolerance induction by stromal cells is reminiscent of central tolerance induced in the thymus by stromal medullary thymic epithelial cells (mTECs), a process that is dependent on PTA expression driven by the autoimmune regulator Aire (70).…”

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

“…For example, liver sinusoidal endothelial cells (LSECs) are thought to capture and cross-present circulating Ag to CD8 + T cells, leading to CD8 + T cell deletion and the establishment of a tolerogenic environment (14). This is especially important in the liver, where LSECs are among the first cells to encounter the large diversity of foreign Ags from food, as well as TLR agonists from commensal sources (15).…”