Department of Immunology, Faculty of Medicine, Technion- Israel Institute of Technology, Haifa, Israel.
Front Immunol. 2020 May 29;11:976. doi: 10.3389/fimmu.2020.00976. eCollection 2020.
CXCR3 is a chemokine receptor with three ligands; CXCL9, CXCL10, and CXCL11. CXCL11 binds CXCR3 with a higher affinity than the other ligands leading to receptor internalization. Long ago we reported that one of these chemokines, CXCL10, not only attracts CXCR3+ CD4+ and CD8+ effector T cells to sites of inflammation, but also direct their polarization into highly potent effector T cells. Later we showed that CXCL11 directs the linage development of T-regulatory-1 cells (Tr1). We also observed that CXCL11 and CXCL10 induce different signaling cascades via CXCR3. Collectively this suggests that CXCR3 ligands differentially regulate the biological function of T cells via biased signaling. It is generally accepted that tumor cells evolved to express several chemokine receptors and secrete their ligands. Vast majority of these chemokines support tumor growth by different mechanisms that are discussed. We suggest that CXCL10 and possibly CXCL9 differ from other chemokines by their ability to restrain tumor growth and enhance anti-tumor immunity. Along with this an accumulating number of studies showed in various human cancers a clear association between poor prognosis and low expression of CXCL10 at tumor sites, and vice versa. Finally, we discuss the possibility that CXCL9 and CXCL10 may differ in their biological function via biased signaling and its possible relevance to cancer immunotherapy. The current mini review focuses on exploring the role of CXCR3 ligands in directing the biological properties of CD4+ and CD8+ T cells in the context of cancer and autoimmunity. We believe that the combined role of these chemokines in attracting T cells and also directing their biological properties makes them key drivers of immune function.
CXCR3 是一种趋化因子受体，有三种配体：CXCL9、CXCL10 和 CXCL11。CXCL11 与 CXCR3 的结合亲和力高于其他配体，导致受体内化。很久以前，我们报道过其中一种趋化因子 CXCL10，不仅吸引 CXCR3+CD4+和 CD8+效应 T 细胞到炎症部位，还直接将其极化成为高效的效应 T 细胞。后来我们发现，CXCL11 指导 T 调节-1 细胞（Tr1）的谱系发育。我们还观察到，CXCL11 和 CXCL10 通过 CXCR3 诱导不同的信号级联反应。总的来说，这表明 CXCR3 配体通过偏向性信号转导差异调节 T 细胞的生物学功能。人们普遍认为，肿瘤细胞进化出表达多种趋化因子受体并分泌其配体的能力。这些趋化因子中的绝大多数通过不同的机制支持肿瘤生长，这些机制正在讨论中。我们认为，CXCL10 和可能的 CXCL9 与其他趋化因子不同，因为它们能够抑制肿瘤生长并增强抗肿瘤免疫。此外，越来越多的研究表明，在各种人类癌症中，肿瘤部位 CXCL10 表达水平低与预后不良之间存在明显关联，反之亦然。最后，我们讨论了 CXCL9 和 CXCL10 通过偏向性信号转导在其生物学功能上可能存在差异及其对癌症免疫治疗的可能相关性。本综述主要探讨了 CXCR3 配体在指导 CD4+和 CD8+T 细胞生物学特性方面在癌症和自身免疫中的作用。我们认为，这些趋化因子在吸引 T 细胞和指导其生物学特性方面的综合作用使它们成为免疫功能的关键驱动因素。
