The Contribution of Non-Professional Antigen-Presenting Cells to Immunity and Tolerance in the Liver

Abstract

The liver represents a unique organ biased toward a tolerogenic milieu. Due to its anatomical location, it is constantly exposed to microbial and food-derived antigens from the gut and thus equipped with a complex cellular network that ensures dampening T-cell responses. Within this cellular network, parenchymal cells (hepatocytes), non-parenchymal cells (liver sinusoidal endothelial cells and hepatic stellate cells), and immune cells contribute directly or indirectly to this process. Despite this refractory bias, the liver is capable of mounting efficient T-cell responses. How the various antigen-presenting cell (APC) populations contribute to this process and how they handle danger signals determine the outcome of the generated immune responses. Importantly, liver mounted responses convey consequences not only for the local but also to systemic immunity. Here, we discuss various aspects of antigen presentation and its consequences by the non-professional APCs in the liver microenvironment.

Keywords: CD1d; antigen presentation; immunoregulation; liver; tolerance.

Figure 1

Non-professional APCs in the liver microenvironment. (A) Presentation of exogenous antigen to CD8⁺ T-cells by hepatocytes leads to T-cell deletion. Via CD1d, hepatocytes can activate iNKT cells. (B) HSCs inhibit DC-mediated activation of CD8⁺ T-cells via CD54 and promote DC-mediated differentiation of CD4⁺ T-cells to T_regs using all-trans retinoid acid. HSCs induce IDO expression in DCs upon direct contact. Additionally, via CD1d HSCs can induce IFNγ secretion in iNKT cells and promote their proliferation by providing IL-15. (C) LSECs promote the differentiation of CD4⁺ T_regs or CD8⁺ memory T-cells, respectively. CD8⁺ memory T-cells migrate to the lymph nodes where they can be reactivated by DCs. LSECs can inhibit DC-mediated antigen presentation via ICAM1 and inhibit T-cell activation via LSECtin. LSECs receive MHC-I antigen complexes from HSCs via transcytosis. (D) In the portal triad, cholangiocytes can activate MAIT cells via MR1 and iNKT cells via CD1d. Additionally, LECs and mast cells could represent a potential cell population with MHC-I and MHC-II antigen-presenting ability. LSECs, liver sinusoidal cells; HSC, hepatic stellate cell; ATRA, all-trans retinoid acid; LEC, lymphatic endothelial cell; MAIT, mucosal-associated invariant T-cell; DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; IFN, interferon; iNKT, invariant natural killer cell; T_regs, regulatory T-cells; MHC, major histocompatibility complex; MR1, MHC class I-like-related molecule; APCs, antigen-presenting cells; LSECs, liver sinusoidal endothelial cells.