Prominent regulatory but weak antigen-presenting cell function of hepatic stellate cells

In their commentary, Alisi et al. emphasize the function of hepatic stellate cells (HSCs) as antigen-presenting cells (APCs) besides their regulatory function.1 As indicated by Alisi et al., HSCs can, in principle, act as APCs for cluster of differentiation (CD)4, CD8, and natural killer T cells.2 It remained unclear how efficiently HSCs function as APCs relative to other hepatic cells, in particular being located in the Dissé space next to liver sinusoidal endothelial cells (LSECs), a well-documented liver-resident APC.3 During conditions of direct competition in vivo, HSCs were less efficient than LSECs in the uptake of circulating antigen from the blood (Fig. 1A). Only dendritic cells (DCs) bear the capacity to function as APC after the uptake of small amounts of antigen. They employ antigen targeting through receptor-mediated endocytosis into intracellular compartments dedicated to cross-presentation in combination with antigen-persistence within these compartments for efficient, prolonged antigen presentation.4, 5 Other cells, such as macrophages, or LSECs need more antigen uptake to cross-present antigen in a similar fashion,6, 7 thus indicating that antigen processing is less efficient, compared to DCs, but compensated by superior antigen uptake. Thus, we next investigated the relative efficiency of HSCs to cross-present antigen to CD8 T cells. Clearly, HSCs were again inferior to LSECs in cross-presentation of circulating antigen ingested in vivo (Fig. 1B). These results demonstrate that HSCs do not possess antigen-processing capability similar to DCs, suggesting that if already antigen uptake is inefficient, downstream mechanisms, such as peptide trimming in the endoplasmic reticulum (ER), are unlikely to improve APC function. A recent report also showed that primary HSCs have little, if any, APC function for CD4 T cells, even after stimulation with exogenous interferon gamma.8 Taken together, these results demonstrate a hierarchy in the performance of APC function for DCs being most efficient in antigen processing, macrophages and LSECs compensating for inefficient antigen processing by high antigen uptake, and HSCs showing low antigen uptake and inefficient antigen processing. These data call into question a prominent role for HSCs as liver-resident APCs. (A) Antigen-uptake by LSECs or HSCs isolated 1 hour after challenge with fluorochrome-labeled ovalbumin (OVA; 4 μg). (B) IL2 release from B3Z-cells recognizing OVA-derived SIINFEKL on H-2Kb after 18 hours coculture with LSECs or HSCs, isolated from mice 1 hour after injection of 1 mg of OVA. Frank A. Schildberg*, Christian Kurts*, Percy A. Knolle MD*, * Institutes of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.