TLR2 Stimulation Strengthens Intrahepatic Myeloid-Derived Cell-Mediated T Cell Tolerance through Inducing Kupffer Cell Expansion and IL-10 Production

Abstract

Hepatic APCs play a critical role in promoting immune tolerance in the liver. Recently, we have demonstrated that TLR2 stimulation on liver sinusoidal endothelial cells reverted their suppressive properties to induce T cell immunity. However, there is a paucity of information about how TLR2 stimulation modulates the immunological function of other hepatic APCs. In the current study, we investigated whether TLR2 stimulation influences the function of intrahepatic myeloid-derived cells (iMDCs) and elucidated the mechanisms involved in iMDC-induced T cell immunity. We could show that iMDCs from C57BL/6 mice can potently suppress T cell activation in a cell contact-independent manner. Ag presentation by iMDCs leads to naive CD8 T cell tolerance. To our surprise, instead of inducing cell functional maturation, TLR2 ligand palmitoyl-3-cysteine-serine-lysine-4 (P3C) stimulation further strengthens the suppressive and tolerogenic properties of iMDCs. After P3C administration, the population of Kupffer cells (KCs) of iMDCs dramatically increased. Mechanism analysis shows that KCs are essential for the enhanced inhibition of T cell activation by P3C-stimulated iMDCs. The iMDC-mediated CD8 T cell inhibition was mediated by soluble mediators, one of which was IL-10 secreted by KCs after P3C stimulation. IL-10 blockade could partially abolish iMDC-mediated T cell inhibition. Moreover, hepatitis B virus particle stimulation on iMDCs could also induce IL-10 production by the cells in a TLR2-dependent way. Our results have implications for our understanding of liver-specific tolerance and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections.

Pre-Activation of Toll-Like Receptor 2 Enhances CD8+ T-Cell Responses and Accelerates Hepatitis B Virus Clearance in the Mouse Models

“…We previously showed that TLR2 activation may also modulate the immune functions of intrahepatic liver sinusoidal endothelial cells (LSECs) ( 32 ). However, we further found that intrahepatic KCs retained the tolerizing activity after TLR2 activation and even increased the IL-10 production ( 33 ). Thus, the recruitment of immune cells into the liver, especially macrophages, may be essential to support T cells as effector cells against HBV ( 20 ).…”

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

“…A direct interaction between HBsAg and KCs with HBsAg uptake, was documented both in vitro and in ex vivo isolated KCs from CHB patients (129). In vitro exposure to HBV antigens preferably induced TGF-β, rather than pro-inflammatory cytokine secretion by primary rat KCs (130); moreover, HBV antigen interaction with TLR2 on KCs caused T cell inhibition through IL-10 secretion (131,132) and TLR2 knockout or KC depletion resulted in enhanced HBV elimination and improved CD8+ T cell responses in mice (131). This inhibitory effect mediated by HBV proteins was further documented by more recent studies showing that HBV protein uptake by intrahepatic macrophages from CHB patients can favor anti-inflammatory over pro-inflammatory functions and can ultimately promote hepatocyte infection (133).…”

Transcriptome Profiling of Bovine Macrophages Infected by Mycobacterium avium spp. paratuberculosis Depicts Foam Cell and Innate Immune Tolerance Phenotypes

“…Beyond both TLR-and TNF-signaling pathways during MAP infection, the classical NFκβ negative feedback system, as schematized in Figure 5, can also induce tolerance. While the endotoxin tolerance is generally mediated by TLR4, other microbial products can stimulate receptors such as TLR2 (116) or TNF receptor (117) to induce crosstolerance. TNF selectively diminished cytokine production in response to subsequent endotoxin challenge (118).…”