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. 1998 Dec;114(3):427-33.
doi: 10.1046/j.1365-2249.1998.00713.x.

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

P A Knolle  1 , A Uhrig, S Hegenbarth, E Löser, E Schmitt, G Gerken, A W Lohse
Affiliations

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

P A Knolle et al. Clin Exp Immunol. 1998 Dec.

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.

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Figures

Fig. 1
Fig. 1
Liver sinusoidal endothelial cells (LSEC) are effective antigen-presenting cells and induce IFN-γ production in CD4+ T cells. LSEC were cultured in flat-bottomed Primaria microtitre plates at a density of 1 × 105 cells/well. At day 5 after isolation antigen-specific CD4+ T cells (LNC.2.F1) (4 × 104/well) were added simultaneously with specific antigen (purified protein derivative) at a concentration of 10 μg/ml. Bone marrow-derived macrophages (BM-macrophages) and Kupffer cells (KC) were seeded at a density of 5 × 104/well and were incubated with LNC2.F1 under identical conditions. After a period of 48 h the cell culture supernatant was assayed for IFN-γ concentration by specific ELISA. All experiments were carried out in triplicates. Results are shown ± s.d.
Fig. 2
Fig. 2
Liver sinusoidal endothelial cells (LSEC) induce antigen-specific T cell proliferation and IFN-γ production in CD4+ T cells. Different cytokines or antibodies were added to LSEC and LNC2.F1 co-cultures. After 48 h the cell culture supernatant was assayed by sandwich ELISA for the concentration of IFN-γ (a). In parallel experiments, methyl-3H-thymidine incorporation was measured during the last 12 h of 72 h of co-culture (b). The measurement of T cell activation using IFN-γ production or methyl-3H-thymidine incorporation as read-out system gave comparable results, but IFN-γ production proved to be more sensitive and reliable. Therefore, only IFN-γ production was determined in later experiments as a measure of T cell activation. All experiments were carried out in triplicates. The results of three separate experiments ± s.e.m. are shown. (c) LSEC were incubated for 24 h with different concentrations of IFN-γ, the cells were thoroughly washed and LNC.2.F1 and purified protein derivative (PPD) were added. IFN-γ concentration was determined after 48 h in cell culture supernatant by sandwich ELISA. One out of five experiments is shown.
Fig. 3
Fig. 3
Down-regulation of T cell activation by IL-10, transforming growth factor-beta (TGF-β) and prostaglandin E2 (PGE2). As described in Fig. 1, liver sinusoidal endothelial cells (LSEC) were co-cultured with antigen-specific T cells (LNC.2.F1) and antigen (purified protein derivative (PPD)). Different cytokines were added and IFN-γ was determined in cell culture supernatant 48 h later (a). IL-10 and PGE2 were added in increasing concentrations to co-cultures of LNC.2.F1, PPD (10 μg/ml) and LSEC (b). IFN-γ concentration was determined as described. The experiment shown is representative of three independent experiments. o, IL-10 (ng/ml); n, PGE2 (μm).
Fig. 4
Fig. 4
The mannose receptor is involved in antigen uptake by liver sinusoidal endothelial cells (LSEC). LSEC were cultured as described on 96-well plates. LSEC were pulsed with purified protein derivative (PPD; 10 μg/ml) for 6 h in the presence of EDTA (a), monensin (b) or mannan (c). Cells were thoroughly washed and LNC.2.F1 were added. Cell culture supernatant was tested for the concentration of IFN-γ after 48 h by ELISA. The experiments shown are representative of three independent experiments. All experiments were carried out in triplicates. Results are shown ± s.d.
Fig. 5
Fig. 5
Mannose receptor activity in liver sinusoidal endothelial cells (LSEC) is down-regulated by IL-10. LSEC were cultured on six-well plates coated with collagen I. LSEC were incubated with dextran–FITC (6 μg/ml) for 3 h in the presence of monensin (3), IL-10 (2) or medium alone (1). For analysis by flow cytometry, LSEC were detached using trypsin/EDTA. For each sample, 2 × 104 cells were analysed. Unlabelled cells were used as a negative control (4). One representative experiment out of three independent experiments is shown.
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References

    1. Calne RY, Sells RA, Pena JR, et al. Induction of immunological tolerance by porcine liver allografts. Nature. 1969;223:472–6. - PubMed
    1. Cantor H, Dumont A. Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature. 1967;215:744. - PubMed
    1. Callery MP, Kamei T, Flye MW. The effect of portacaval shunt on delayed-hypersensitivity responses following antigen feeding. J Surg Res. 1989;46:391–4. - PubMed
    1. Yang R, Liu Q, Grosfeld JL, Pescovitz MD. Intestinal venous drainage through the liver is a prerequisite for oral tolerance induction. J Pediatr Surg. 1994;29:1145–8. - PubMed
    1. Altman A, Coggeshall KM, Mustelin T. Molecular events mediating T cell activation. Adv Immunol. 1990;48:227–360. - PubMed

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