Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, New York 10065, USA.
J Biol Chem. 2011 Feb 4;286(5):3970-80. doi: 10.1074/jbc.M110.159392. Epub 2010 Oct 27.
Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to deliver antigens for presentation on major histocompatibility complex (MHC) class II molecules. Skeletal muscle fibers show a high level of constitutive macroautophagy and express MHC class II molecules upon immune activation. We found that tumor necrosis factor-α (TNF-α), a monokine overexpressed in inflammatory myopathies, led to a marked up-regulation of macroautophagy in skeletal myocytes. Furthermore, TNF-α augmented surface expression of MHC class II molecules in interferon-γ (IFN-γ)-treated myoblasts. The synergistic effect of TNF-α and IFN-γ on the induction of MHC class II surface expression was not reflected by higher intracellular human leukocyte antigen (HLA)-DR levels and was reversed by macroautophagy inhibition, suggesting that TNF-α facilitates antigen processing via macroautophagy for more efficient MHC class II loading. Muscle biopsies from patients with sporadic inclusion body myositis, a well defined myopathy with chronic inflammation, showed that over 20% of fibers that contained autophagosomes costained for MHC class II molecules and that more than 40% of double-positive muscle fibers had contact with CD4(+) and CD8(+) immune cells. These findings establish a mechanism through which TNF-α regulates both macroautophagy and MHC class II expression and suggest that macroautophagy-mediated antigen presentation contributes to the immunological environment of the inflamed human skeletal muscle.
自噬作用是一种将细胞质成分输送到内体和溶酶体隔室的稳态过程，最近已经证明它可以将抗原递呈到主要组织相容性复合体 (MHC) Ⅱ类分子上。骨骼肌纤维表现出高水平的组成型自噬作用，并在免疫激活时表达 MHC Ⅱ类分子。我们发现，肿瘤坏死因子-α（TNF-α），一种在炎症性肌病中过度表达的单核因子，导致骨骼肌细胞中的自噬作用明显上调。此外，TNF-α增强了干扰素-γ（IFN-γ）处理的成肌细胞表面 MHC Ⅱ类分子的表达。TNF-α和 IFN-γ对 MHC Ⅱ类表面表达的协同作用并未反映在细胞内人白细胞抗原（HLA）-DR 水平的升高上，并且可以通过自噬作用抑制来逆转，这表明 TNF-α通过自噬作用促进抗原加工，以更有效地加载 MHC Ⅱ类分子。来自散发性包涵体肌炎患者的肌肉活检显示，一种具有慢性炎症的明确肌病，超过 20%的含有自噬体的纤维与 MHC Ⅱ类分子共染色，超过 40%的双阳性肌纤维与 CD4(+)和 CD8(+)免疫细胞接触。这些发现建立了一种机制，通过该机制，TNF-α调节自噬作用和 MHC Ⅱ类表达，并表明自噬作用介导的抗原呈递有助于人类炎症骨骼肌的免疫环境。
