Viñas Odette, Bataller Ramón, Sancho-Bru Pau, Ginès Pere, Berenguer Cristina, Enrich Carlos, Nicolás Josep M, Ercilla Guadalupe, Gallart Teresa, Vives Jordi, Arroyo Vicente, Rodés Juan
Laboratory of Immunology, Hospital Clínic, University of Barcelona School of Medicine, Institut d'Investigacios Biomèdiques August Pi-Sunyer (IDIBAPS), Villaroel 170, 08036 Barcelona, Catalonia, Spain.
Hepatology. 2003 Oct;38(4):919-29. doi: 10.1053/jhep.2003.50392.
Following cell activation, hepatic stellate cells (HSCs) acquire proinflammatory and profibrogenic properties. We investigated whether activated HSCs also display immune properties. Here we show that cultured human HSCs express membrane proteins involved in antigen presentation, including members of the HLA family (HLA-I and HLA-II), lipid-presenting molecules (CD1b and CD1c), and factors involved in T-cell activation (CD40 and CD80). Exposure of HSCs to proinflammatory cytokines markedly up-regulates these molecules. Importantly, cells freshly isolated from human cirrhotic livers (in vivo activated HSCs) highly express HLA-II and CD40, suggesting that HSCs can act as antigen-presenting cells (APCs) in human fibrogenesis. We also explored whether human HSCs can efficiently process exogenous antigens. Activated HSCs internalize low- and high-molecular-weight dextran and transferrin, indicating that they can perform fluid-phase and receptor-mediated endocytosis. Moreover, HSCs can perform phagocytosis of macromolecules because they internalize latex particles as well as bacteria. Interestingly, both culture-activated and in vivo activated HSCs express high levels of CD68, a protein involved in antigen trafficking. Finally, we studied whether HSCs modulate T-lymphocyte proliferation. In basal conditions, coculture of irradiated HSCs barely induces allogeneic T-lymphocyte proliferation. However, cytokine-stimulated HSCs stimulate the allogeneic T-lymphocyte response in an HLA-II-dependent manner. In conclusion, human activated HSCs express molecules for antigen presentation, internalize macromolecules, and modulate T-lymphocyte proliferation. These results suggest that HSCs may play a role in the immune function of the liver.
细胞活化后，肝星状细胞（HSCs）获得促炎和促纤维化特性。我们研究了活化的HSCs是否也具有免疫特性。在此我们表明，培养的人HSCs表达参与抗原呈递的膜蛋白，包括HLA家族成员（HLA-I和HLA-II）、脂质呈递分子（CD1b和CD1c）以及参与T细胞活化的因子（CD40和CD80）。将HSCs暴露于促炎细胞因子可显著上调这些分子的表达。重要的是，从人类肝硬化肝脏中新鲜分离的细胞（体内活化的HSCs）高表达HLA-II和CD40，这表明HSCs在人类纤维化过程中可作为抗原呈递细胞（APCs）发挥作用。我们还探究了人HSCs是否能够有效处理外源性抗原。活化的HSCs可内化低分子量和高分子量的葡聚糖以及转铁蛋白，表明它们能够进行液相和受体介导的内吞作用。此外，HSCs能够吞噬大分子，因为它们可内化乳胶颗粒以及细菌。有趣的是，培养活化的和体内活化的HSCs均高表达CD68，这是一种参与抗原转运的蛋白。最后，我们研究了HSCs是否调节T淋巴细胞增殖。在基础条件下，照射后的HSCs与异基因T淋巴细胞共培养几乎不诱导其增殖。然而，细胞因子刺激的HSCs以HLA-II依赖的方式刺激异基因T淋巴细胞反应。总之，人活化的HSCs表达抗原呈递分子，内化大分子，并调节T淋巴细胞增殖。这些结果表明HSCs可能在肝脏的免疫功能中发挥作用。
