Human hepatic stellate cells are liver-resident antigen-presenting cells
Authors: Anna Alisi, Paolo Romania, Valerio Nobili, Franco Locatelli, Doriana Fruci
Journal: Hepatology (2011)

We read with great interest the article published in this journal by Schildberg et al.1 In this study, the investigators demonstrated that hepatic stellate cells (HSCs) veto naïve cluster of differentiation (CD)8+ T-cell priming through a cell-contact–dependent mechanism, and that this novel HSC function is dependent on their activation state. High expression levels of CD54 on HSCs correlated with impaired expression of interleukin (IL)-2 receptor and IL-2 production in T cells. The take-home message of this study is the identification of a direct role of HSCs in controlling nonmajor histocompatibility complex (MHC)-restricted dependent immune tolerance. Although this study reveals a novel, interesting immunological function of HSCs, here, we want to call attention also to their potential role as antigen-presenting cells (APCs). Winau et al.2 demonstrated that HSCs are intrahepatic APCs activating T cells and eliciting a multiplicity of T-cell responses. More recently, Bomble et al.3 demonstrated that, even though the function of HSCs as APCs might be secondary in healthy liver and reduced during epithelial-mesenchymal transition, in vitro stimulation with interferon gamma (IFN-γ) induces the expression of MHC class II and restores their antigen-presenting functionality. Here, we reinforce the data on the potential role of HSCs as APCs by demonstrating that these cells express high levels of two components of the antigen processing machinery: the endoplasmic reticulum (ER) aminopeptidases, ERAP1 and ERAP2, which have been shown to optimize precursor peptides for binding to MHC class I molecules.4 As expected, the human HSC line, LX-2, in basal conditions expresses high levels of surface MHC class I and low levels of surface MHC class II molecules (Fig. 1A). IFN-γ stimulation resulted in the surface enhancement of both MHC class I and MHC class II molecules. Interestingly, MHC class I overexpression, also confirmed by immunoblotting, was associated with the up-regulation of both ERAP1 and ERAP2 (Fig. 1B). IFN-γ enhances antigen-processing/presenting functionality of LX-2 cells. (A) Flow cytometric analysis of MHC class I and MHC class II molecules in LX-2 cells grown in serum-free medium in the absence (gray lines) and presence (black lines) of 500 U/mL of IFN-γ for 6 days. Shaded histograms, isotype-matched negative controls. (B) MHC class I, ERAP1, and ERAP2 immunoblotting in LX-2 cells treated as in (A) ERp57 was used for normalization. Altogether, these results, in agreement with previous studies,2, 3 demonstrate that HSCs are liver resident APCs with the capability to induce hepatic T-cell immunity by MHC-restricted interaction. Finally, these findings, as well as those presented by Schildberg et al., suggest that therapeutic strategies aiming to recover or increase MHC-restricted and/or non-MHC-restricted antigen-presenting functionality of HSCs may provide opportunities to devise immunotherapy strategies toward enhancing the ability of T lymphocytes to recognize and kill tumor cells. Anna Alisi Ph.D.*, Paolo Romania , Valerio Nobili*, Franco Locatelli , Doriana Fruci , * Liver Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy, Oncohaematology Department, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy, University of Pavia, Pavia, Italy.