Antigen processing-Cross presentation

MHC class I molecules generally present peptide antigens derived from proteins synthesized by the cell itself to CD8+ T cells. However, in some circumstances, antigens from extracellular environment can be presented on MHC class I to stimulate CD8+ T cell immunity, a process termed cross-presentation (Rock & Shen. 2005). Cross-presentation/cross-priming is the ability of antigen presenting cells (APCs) to present exogenous antigens on MHC class I molecules to CD8+ T lymphocytes. Among all the APCs, dendritic cells (DC) are the dominant antigen cross presenting cell types in vivo, although macrophages and B cells appear to cross present model antigens in vitro with a low degree of efficiency (Amigorena & Savina. 2010, Ackermann & Peter Cresswell. 2004). Compared to macrophages, DCs have low levels of lysosomal proteases and exhibit limited lysosomal degradation (Delamarre et al. 2005). This limited proteolysis of internalized antigens by DCs might contribute to their high efficiency for cross-presentation (Monua & Trombetta. 2007). APCs acquire the exogenous antigens through endocytic mechanisms, especially phagosomes for particulate/cell-associated antigens and endosomes for soluble protein antigens. There does not seem to be a unique pathway for cross-presentation but rather different potential mechanisms of cross-presentation have been proposed. These proposed pathways can be classified according to the location where two key events occur: 1) processing of the antigenic protein and 2) loading of the processed peptide on to MHC I molecule (Blanchard & Shastri. 2010). Based on the requirement for TAP and cytosolic proteases two mechanisms have been described, a cytosolic pathway (TAP-dependent and proteasome-dependent) or a vacuolar pathway (TAP- and proteasome-independent) (Blanchard & Shastri. 2010, Amigorena & Savina. 2010). Regarding peptide-loading, MHC I could be loaded in the ER or in the phagosome and recycled to cell surface (Blanchard & Shastri. 2010). Exogenous soluble antigens are cross-presented by dendritic cells, albeit with lower efficiency than for particulate substrates. Soluble antigens destined for cross-presentation are taken up by distinct endocytosis mechanisms which route them into stable early endosomes and then to the cytoplasm for proteasomal degradation and peptide loading. The outcome of the cross-presentation can be either tolerance or immunity (Rock & Shen. 2005).

MHC I 类分子通常呈递由细胞自身合成的蛋白质来源的肽抗原给 CD8+ T 细胞。然而，在某些情况下，源自细胞外环境的抗原可以呈递在 MHC I 类分子上以刺激 CD8+ T 细胞免疫，此过程被称为交叉呈递（Rock & Shen. 2005）。交叉呈递/交叉致敏是抗原呈递细胞（APCs）在 MHC I 类分子上呈递外源性抗原给 CD8+ T 淋巴细胞的能力。在所有 APCs 中，树突状细胞（DCs）是体内主要的抗原交叉呈递细胞类型，尽管巨噬细胞和B细胞似乎在体外以低效度交叉呈递模型抗原（Amigorena & Savina. 2010，Ackermann & Peter Cresswell. 2004）。与巨噬细胞相比，DCs 具有低水平的溶酶体蛋白酶，并表现出有限的溶酶体降解（Delamarre et al. 2005）。DCs 对内化抗原的有限蛋白水解作用可能有助于其交叉呈递的高效性（Monua & Trombetta. 2007）。APCs 通过内吞作用机制获取外源性抗原，特别是针对颗粒/细胞相关抗原的吞噬体和针对可溶性蛋白抗原的晚期内吞体。似乎不存在交叉呈递的特异性途径，而是提出了不同的交叉呈递潜在机制。这些提出的途径可以根据两个关键事件发生的位置进行分类：1）抗原蛋白的处理和2）处理后的肽加载到 MHC I 分子上（Blanchard & Shastri. 2010）。基于对 TAP 和细胞质蛋白酶的需求，已描述了两种机制：一种细胞质途径（TAP 依赖性和蛋白酶体依赖性）或一种溶酶体途径（TAP 和蛋白酶体非依赖性）（Blanchard & Shastri. 2010，Amigorena & Savina. 2010）。至于肽加载，MHC I 可能在内质网或吞噬体中加载并循环至细胞表面（Blanchard & Shastri. 2010）。尽管外源性可溶性抗原的交叉呈递效率低于颗粒底物，但树突状细胞仍能进行交叉呈递。预定用于交叉呈递的可溶性抗原通过特定的内吞作用机制摄取，并被路由到稳定的早期内吞体，然后进入细胞质进行蛋白酶体降解和肽加载。交叉呈递的结果可能是耐受或免疫（Rock & Shen. 2005）。