Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses
Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses
复制标题
DOI：
10.4049/jimmunol.0901573
复制
发表时间：
2009-12-01
影响因子：
4.4
通讯作者：
Schirmbeck, Reinhold
中科院分区：
文献类型：
--
作者：
Brosi, Helen;Reiser, Michael;Schirmbeck, Reinhold
RIP-B7.1小鼠在胰岛β细胞上表达共刺激分子B7.1(CD80)，是研究糖尿病CD8 T细胞从头诱导的成熟模型。用编码胰岛素原(Ppins)的质粒DNA免疫RIP-B7.1小鼠可有效诱导实验性自身免疫性糖尿病(EAD)。EAD与K-b/A(12-21)表位特异性CD8 T细胞进入胰岛并随后破坏β细胞有关。在这项研究中，我们使用这个模型来研究ppins来源的AGs是如何表达和加工成初始的、导致糖尿病的K-b/A(12-21)特异性CD8T细胞的。靶向K-b/A(12-21)表位、胰岛素A链或内质网(ER)的多肽(但不是胞浆和/或细胞核)可有效地激发K-b/A(12-21)特异性CD8T细胞应答。K-b/A(12-21)表位代表PPINS分子的COOH末端，因此在与其限制元件结合在内质网之前不需要COOH末端处理。然而，在内质网中表达的COOH末端延伸的ppins特异性多肽也诱导了K-b/A(12-21)特异性CD8T细胞，这表明COOH末端的表位位置对其糖尿病致病作用不如将抗原靶向内质网重要。K-b/A(12-21)表位对K-b分子亲和力较低。当不相关的AGS的表位在同一个Ag传递部位共表达时，“强烈的”K-b限制性(但不是D-b限制性)CD8T细胞反应导致K-b/A(12-21)特异性CD8T细胞的启动被抑制，EAD降低。因此，在内质网中直接表达和加工“弱”K-b/A(12-21)表位有利于自身反应性CD8T细胞的启动。免疫学杂志，2009,183：7187-7195。
RIP-B7.1 mice express the costimulator molecule B7.1 (CD80) on pancreatic beta cells and are a well-established model for studying de novo induction of diabetogenic CD8 T cells. Immunization of RIP-B7.1 mice with preproinsulin (ppins)-encoding plasmid DNA efficiently induces experimental autoimmune diabetes (EAD). EAD is associated with an influx of CD8 T cells specific for the K-b/A(12-21) epitope into the pancreatic islets and the subsequent destruction of beta cells. In this study, we used this model to investigate how ppins-derived Ags are expressed and processed to prime diabetogenic, K-b/A(12-21)-specific CD8 T cells. Targeting the K-b/A(12-21) epitope, the insulin A chain, or the ppins to the endoplasmic reticulum (ER) (but not to the cytosol and/or nucleus) efficiently elicited K-b/A(12-21)-specific CD8 T cell responses. The K-b/A(12-21) epitope represents the COOH-terminus of the ppins molecule and, hence, did not require COOH-terminal processing before binding its restriction element in the ER. However, K-b/A(12-21)-specific CD8 T cells were also induced by COOH-terminally extended ppins-specific polypeptides expressed in the ER, indicating that the epitope position at the COOH terminus is less important for its diabetogenicity than is targeting the Ag to the ER. The K-b/A(12-21) epitope had a low avidity for K-b molecules. When epitopes of unrelated Ags were coprimed at the same site of Ag delivery, "strong" K-b-restricted (but not D-b-restricted) CD8 T cell responses led to the suppression of K-b/A(12-21)-specific CD8 T cell priming and reduced EAD. Thus, direct expression and processing of the "weak" K-b/A(12-21) epitope in the ER favor priming of autoreactive CD8 T cells. The Journal of Immunology, 2009, 183: 7187-7195.