Tinoco Roberto, Carrette Florent, Barraza Monique L, Otero Dennis C, Magaña Jonathan, Bosenberg Marcus W, Swain Susan L, Bradley Linda M
Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Infectious and Inflammatory Disease Center and NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037, USA.
Immunity. 2016 May 17;44(5):1190-203. doi: 10.1016/j.immuni.2016.04.015.
Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, P-selectin glycoprotein ligand-1 (PSGL-1), that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4(+)-T-cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8(+) T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology and also functions to regulate T cell responses in the tumor microenvironment.
慢性病毒和癌症通过诱导T细胞功能障碍来阻碍人类的免疫反应。我们使用一种模拟人类感染的小鼠慢性病毒，研究了在反应性T细胞上上调的粘附分子P-选择素糖蛋白配体-1（PSGL-1）的功能。PSGL-1缺陷小鼠清除了病毒，这是由于多功能效应T细胞的内在存活率增加，这些T细胞下调了PD-1以及其他抑制性受体。值得注意的是，这种反应导致了CD4(+) T细胞依赖性免疫病理学。从机制上讲，耗尽的CD8(+) T细胞上的PSGL-1连接抑制了T细胞受体（TCR）和白细胞介素-2（IL-2）信号传导，并上调了PD-1，导致TCR刺激下存活率降低。在发生T细胞功能障碍的黑色素瘤癌症模型中，PSGL-1缺陷导致PD-1下调、T细胞反应改善和肿瘤控制。因此，PSGL-1在平衡病毒控制和免疫病理学方面发挥着重要作用，并且在肿瘤微环境中也起到调节T细胞反应的作用。
