IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules

Abstract

Our study demonstrates that antigen-presenting liver sinusoidal endothelial cells (LSEC) induce production of interferon-gamma (IFN-gamma) from cloned Th1 CD4+ T cells. We show that LSEC used the mannose receptor for antigen uptake, which further strengthened the role of LSEC as antigen-presenting cell (APC) population in the liver. The ability of LSEC to activate cloned CD4+ T cells antigen-specifically was down-regulated by exogenous prostaglandin E2 (PGE2) and by IL-10. We identify two separate mechanisms by which IL-10 down-regulated T cell activation through LSEC. IL-10 decreased the constitutive surface expression of MHC class II as well as of the accessory molecules CD80 and CD86 on LSEC. Furthermore, IL-10 diminished mannose receptor activity in LSEC. Decreased antigen uptake via the mannose receptor and decreased expression of accessory molecules may explain the down-regulation of T cell activation through IL-10. Importantly, the expression of low numbers of antigen on MHC II in the absence of accessory signals on LSEC may lead to induction of anergy in T cells. Because PGE2 and IL-10 are released from LSEC or Kupffer cells (KC) in response to those concentrations of endotoxin found physiologically in portal venous blood, it is possible that the continuous presence of these mediators and their negative effect on the local APC may explain the inability of the liver to induce T cell activation and to clear chronic infections. Our results support the notion that antigen presentation by LSEC in the hepatic microenvironment contributes to the observed inability to mount an effective cell-mediated immune response in the liver.

Dermal Microvascular Endothelial Cells Express the 180-kDa Macrophage Mannose Receptor In Situ and In Vitro

“…Upon further subculture, MR surface expression decreased and was virtually absent at passage 5. MR expression could not be maintained or reinduced with cytokines such as IL-4, IL-10, IL-13, IFN, and TNF, which are known to enhance MR expression on macrophages and sinusoidal liver endothelium (20,31,32) (data not shown). The correct m.w.…”

“…They express another scavenger receptor, CD32 (Fc␥RIIa), and their role in Ag capture and clearing is well characterized (17,18). They constitutively express MHC class II molecules, which suggests that they are involved not only in Ag uptake but also in Ag presentation (19,20). Human dermal microvascular endothelial cells (DMEC) also constitutively express CD32 and MHC class II molecules and thus appear to share some of the properties of sinusoidal liver endothelium in playing a role in Ag capture/clearing and presentation (21)(22)(23)(24).…”

Role of mucosal dendritic cells in inflammatory bowel disease

“…Further, the presence of CD8α + CD11b -and CD8α -CD11b + DCs has been reported [78] . The continuous exposure of resident APCs with the bacterial cell wall derived LPS promotes the induction of CD4 regulatory T cells and may explain the dominance of IL-10 in the liver [79,80] . If Kupffer cells are depleted by gadolonium chloride treatment, liver tolerance becomes impaired raising the possibility that the liver is increasingly recognized as an innate and adaptive immune organ [81] .…”

Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection

“…For example, interleukin 10 (IL-10) is a potent anti-inflammatory Th2 cytokine that down-regulates the expression of major histocompatibility complex (MHC) class I and class II molecules as well as the production of Th1 cytokines. [6][7][8][9][10][11][12] IL-10 levels differ widely between individuals, possibly because of polymorphisms in the promoter region of the IL-10 gene. 13,14 Specifically, 3 single nucleotide polymorphisms (SNPs) in the promoter (at positions Ϫ1082, Ϫ819, and Ϫ592 relative to the transcription start site) 15 form 3 SNP combinations (ATA, ACC, GCC) associated with differential IL-10 expression.…”