Presentation of metabolites by the major histocompatibility complex class I–related protein 1 (MR1) molecule to mucosal-associated invariant T cells is impaired during herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating the intracellular pool of immature MR1, effectively inhibiting new surface antigen presentation, while preexisting ligand-bound mature MR1 is surprisingly upregulated by HSV-1. Using flow cytometry, immunoblotting, and high-throughput fluorescence microscopy, we demonstrate that the endocytosis of surface MR1 is impaired during HSV infection and that internalized molecules accumulate in EEA1-labeled early endosomes, avoiding degradation. We establish that the short MR1 cytoplasmic tail is not required for HSV-1–mediated downregulation of immature molecules; however it may play a role in the retention of mature molecules on the surface and in early endosomes. We also determine that the HSV-1 US3 protein, the shorter US3.5 kinase and the full-length HSV-2 homolog, all predominantly target mature surface rather than total MR1 levels. We propose that the downregulation of intracellular and cell surface MR1 molecules by US3 and other HSV proteins is an immune-evasive countermeasure to minimize the effect of impaired MR1 endocytosis, which might otherwise render infected cells susceptible to MR1-mediated killing by mucosal-associated invariant T cells.

中文翻译：

---

早期内体区室中的内吞作用和积累受损定义了单纯疱疹病毒介导的非经典 MHC I 类相关分子 MR1 的破坏


在单纯疱疹病毒 1 型 (HSV-1) 和 2 型 (HSV-2) 感染期间，主要组织相容性复合物 I 类相关蛋白 1 (MR1) 分子向粘膜相关的不变 T 细胞呈递代谢物受到损害。鉴于这些病毒不直接合成 MR1 配体，这是令人惊讶的。我们之前已经鉴定出几种 HSV 蛋白负责快速下调细胞内未成熟 MR1 池，有效抑制新的表面抗原呈递，而先前存在的配体结合的成熟 MR1 令人惊讶地被 HSV-1 上调。使用流式细胞术、免疫印迹和高通量荧光显微镜，我们证明表面 MR1 的内吞作用在 HSV 感染期间受损，并且内化分子在 EEA1 标记的早期内涵体中积累，避免了降解。我们确定，HSV-1 介导的未成熟分子下调不需要短 MR1 胞质尾；然而，它可能在成熟分子保留在表面和早期内体中发挥作用。我们还确定 HSV-1 US3 蛋白、较短的 US3.5 激酶和全长 HSV-2 同源物均主要靶向成熟表面而不是总 MR1 水平。我们认为，US3 和其他 HSV 蛋白对细胞内和细胞表面 MR1 分子的下调是一种免疫逃避对策，可最大限度地减少 MR1 内吞作用受损的影响，否则可能会使受感染的细胞容易受到粘膜相关不变量介导的 MR1 介导的杀伤作用。 T细胞。