T细胞可以表达多种抑制性受体。当 T 细胞对持久性抗原做出反应而耗尽时，尤其是在抗肿瘤免疫反应中，许多抗原同时表达。关键抑制性受体是 CTLA-4、PD-1、LAG3、TIM3 和 TIGIT，如下所示。这些受体作为癌症免疫治疗的中心治疗靶点非常重要。抑制性受体并不在细胞表面组成型表达，但大部分存在于细胞内囊泡结构中。不同抑制性受体的亚细胞定位在多大程度上是不同的，这一点仍未解决。使用亚细胞分布和质膜插入的定量成像，并辅以抑制性受体与运输接头关联的邻近蛋白质组学和生化分析，五种抑制性受体的亚细胞分布是离散的。 CTLA-4 的分布最为明显，优先与溶酶体来源的囊泡和分选连接蛋白 1/2/5/6 转运机制相关。由于缺乏特定囊泡亚型存在的证据来解释不同的抑制性受体分布，我们认为这种分布是由通过一组重叠的囊泡结构的不同运输驱动的。对五种抑制性受体相互关系的亚细胞定位的广泛表征为其运输及其治疗开发的分子研究奠定了基础。

T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to a persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3, and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct, with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation.