Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER), bind to major histocompatibility type I (MHC-I) protein complexes, and are transported to the cell surface for cross-presentation. DCs can exhibit activation of the ER stress sensor IRE1α without ER stress, but the underlying mechanism remains obscure. Here, we show that antigen-derived hydrophobic peptides can directly engage ER-resident IRE1α, masquerading as unfolded proteins. IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti–PD-L1 antibody treatment to cause tumor regression. Our findings identify an unexpected cell-biological mechanism of antigen-driven IRE1α activation in DCs, revealing translational potential for cancer immunotherapy.

中文翻译：

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抗原衍生肽与 ER 应激传感器 IRE1α 结合以抑制树突状细胞交叉呈递

树突状细胞 (DC) 通过将基于抗原的表位交叉呈递给 CD8+ T 细胞来促进适应性免疫。DC 将内化的蛋白质抗原加工成肽，进入内质网 (ER)，与主要组织相容性 I 型 (MHC-I) 蛋白质复合物结合，并转运到细胞表面进行交叉呈递。DCs 可以在没有 ER 应激的情况下激活 ER 应激传感器 IRE1α，但其潜在机制仍不清楚。在这里，我们证明抗原衍生的疏水性肽可以直接与内质网驻留的 IRE1α 结合，伪装成未折叠的蛋白质。IRE1α 激活通过受调节的 IRE1α 依赖性衰变 (RIDD) 耗尽 MHC-I 重链 mRNA，从而减少抗原交叉呈递。在荷瘤小鼠中，IRE1α 破坏增加了肿瘤浸润 DC 上的 MHC-I 表达，并增强了 CD8+ T 细胞的募集和激活。此外，IRE1α 抑制与抗 PD-L1 抗体治疗协同作用，导致肿瘤消退。我们的研究结果确定了 DC 中抗原驱动的 IRE1α 激活的一种意想不到的细胞生物学机制，揭示了癌症免疫治疗的转化潜力。