PDF(Pubmed)
Abstract：
Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.
摘要：
T细胞受体（TCR）发出的信号，共刺激受体，和细胞因子受体各自影响CD8T细胞命运。了解这些信号对稳态和微环境线索的反应可以揭示治疗性指导T细胞功能的新方法。通过小鼠的正向遗传筛查，我们发现LDL受体相关蛋白10(Lrp10)的功能缺失突变导致幼稚和中枢记忆性CD8T细胞在外周淋巴器官中积累.Lrp10编码免疫功能未知的保守细胞表面蛋白。T细胞活化诱导Lrp10表达，它在翻译后抑制IL7受体（IL7R）水平。因此，Lrp10缺失通过IL7R信号增强T细胞稳态扩增。Lrp10缺陷型小鼠也对同基因肿瘤具有内在抗性。这种表型取决于CD8T细胞的致密肿瘤浸润，显示出增强的存储单元特性，减少终端疲惫，和增强对免疫检查点抑制的反应。这里,我们提出Lrp10作为CD8T细胞稳态的一种新的负调节因子和一种控制肿瘤耐药的宿主因子,对免疫治疗有意义.
