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

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 antige n 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 prosta glandin E-2 (PGE(2)) and by IL-10. We identify two separate mechanisms by w hich IL-10 down-regulated T cell activation through LSEC. IL-10 decreased t he constitutive surface expression of MHC class II as well as of the access ory molecules CD80 and CD86 on LSEC. Furthermore, IL-10 diminished mannose receptor activity in LSEC. Decreased antigen uptake via the mannose recepto r and decreased expression of accessory molecules may explain the down-regu lation of T cell activation through IL-IO. Importantly, the expression of l ow numbers of antigen on MHC II in the absence of accessor; signals on LSEC may lead to induction of anergy in T cells. Because PGE(2) and IL-10 are r eleased 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 o n the local APC may explain the inability of the liver to induce T cell act ivation and to clear chronic infections. Our results support the notion tha t antigen presentation by LSEC in the hepatic microenvironment contributes to the observed inability to mount an effective cell-mediated immune respon se in the liver.