Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells

Abstract

U nder physiological conditions, the liver is basically free of inflammation and the resident antigen-presenting cells (APC) of the liver are believed to actively participate in the maintenance of hepatic immune tolerance. 1 Indeed, the most prevalent professional APC in liver, liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC), 2,3 have been shown to actively induce immune tolerance. 2,4,5 In addition, hepatocytes, which can upregulate expression of class II molecules of the major histocompatibility complex (MHC II) during hepatitis 6 and may then serve as APC for CD4 ϩ T lymphocytes, 7 also have been implicated in the induction of immune tolerance. 8 Nevertheless, rapid infiltration of the liver with inflammatory cells is induced during infection. However, the mechanisms that mediate the transition from hepatic immune tolerance to hepatic inflammation are not clear.CD4 ϩ CD25 ϩ regulatory T cells (Treg) are important mediators of peripheral immune tolerance: Treg can suppress the activation of autoreactive CD4 ϩ and CD8 ϩ T cells [9][10][11] and also control immune responses during infection. 12,13 Whether Treg are involved in the maintenance of hepatic immune tolerance is not clear; however, recent reports indicate that Treg indeed may suppress hepatic immunity to autoantigen 14 or virus. 15 Thus, it is likely that local suppressive Treg activity needs to be attenuated before liver inflammation can be induced.It has been reported recently that splenic dendritic cells have the capacity to regulate the suppressive activity of Treg 16 : normally, dendritic cells stimulate Treg-mediated suppression; however, in response to microbial stimuli, like lipopolysaccharide (LPS) or immune-stimulatory oli-

A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury

“…Because Tregs play an important role in maintaining the immune regulation of hepatic inflammatory activity, 35 their depletion leads to increased inflammation and activation of the TNF-␣ signaling pathway, resulting in further liver injury when the liver is exposed to LPS, which can be endogenously produced by intestinal flora and delivered to the liver. 27 These downstream effects of ROS-induced Treg modulation further contribute to the inflammatory process in steatosis.…”

Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota

“…Using a mouse model, signaling through the CpG-DNA/TLR9 pathway enabled hepatic expansion of HBV-specific cytotoxic CD8+ T cells which, in turn, eradicated HBV-infected hepatocytes during chronic infection, leading to viral clearance (22). During microbial infection, KCs and LSECs were observed to override the tolerance phenotype and promote CD4+ T-cell proliferation in the presence of TLR ligands, such as LPS and CpG-DNA (23). The interaction between Significance Ninety-five percent of adult-acquired infections lead to spontaneous clearance, whereas >90% of exposed neonates and ∼30% of children aged 1-5 y fail to resolve hepatitis B virus (HBV) and develop chronic infection.…”

Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

“…11,12 Although CXCR3 is preferentially associated with a Th1 phenotype, 7 CXCL9 also promotes transmigration of Th2 cells. 10 Against the background of the particular immunological capacity of the liver to support the induction of peripheral tolerance rather than to establish immunity, 13,14 we hypothesized whether LSEC might possess distinct gatekeeper functions for leukocytes. Here we used a transwell assay system and time-lapse microscopy with ex vivo isolated murine LSEC to investigate whether LSEC inhibit or support the chemokine-driven transmigration of CD4 ϩ T cells.…”