Laboratoire d'Immunologie Moléculaire, Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
Immunol Cell Biol. 2012 Oct;90(9):896-902. doi: 10.1038/icb.2012.27. Epub 2012 Jun 12.
The invariant chain (Ii) has pleiotropic functions and is a key factor in antigen presentation. Ii associates with major histocompatibility complex class II molecules in the endoplasmic reticulum (ER) and targets the complex in the endocytic pathway to allow antigenic peptide loading. The human Iip35 isoform includes a cytoplasmic extension containing a di-arginine motif causing ER retention. This minor isoform does not exist in mice and its function in humans has not been thoroughly investigated. We have recently generated transgenic mice expressing Iip35 and these were crossed with Ii-deficient mice to generate animals (Tgp35/mIiKO) expressing exclusively the human isoform. In these mice, we show that Iip35 is expressed in antigen presenting cells and is inducible by interferon gamma (IFN-γ). Despite the low constitutive expression of the protein and some minor differences in the Vβ repertoire of Tgp35/mIiKO mice, Iip35 restored thymic selection of CD4(+) T cells and of invariant natural killer T cells. In vitro functional assays using purified primary macrophages treated with IFN-γ showed that Iip35 allows presentation of an Ii-dependent ovalbumin T-cell epitope. Altogether, our results suggest that Iip35 is functional and does not require co-expression of other isoforms for antigen presentation.
不变链 (Ii) 具有多种功能，是抗原呈递的关键因素。Ii 在内质网 (ER) 中与主要组织相容性复合体 II 分子结合，并将复合物靶向内体途径，以允许抗原肽加载。人类 Iip35 同种型包括一个含有二精氨酸基序的细胞质延伸部分，导致 ER 滞留。这种次要同种型在小鼠中不存在，其在人类中的功能尚未得到彻底研究。我们最近生成了表达 Iip35 的转基因小鼠，并将其与 Ii 缺陷型小鼠杂交，以生成仅表达人类同种型的动物 (Tgp35/mIiKO)。在这些小鼠中，我们表明 Iip35 在抗原呈递细胞中表达，并可被干扰素 γ (IFN-γ) 诱导。尽管该蛋白的组成性表达水平较低，并且 Tgp35/mIiKO 小鼠的 Vβ 库存在一些细微差异，但 Iip35 恢复了 CD4(+) T 细胞和固有自然杀伤 T 细胞的胸腺选择。使用 IFN-γ 处理的纯化原代巨噬细胞进行的体外功能测定表明，Iip35 允许呈递依赖于 Ii 的卵清蛋白 T 细胞表位。总之，我们的结果表明 Iip35 具有功能，并且不需要其他同种型的共表达即可进行抗原呈递。
