Extended Co-Expression of Inhibitory Receptors by Human CD8 T-Cells Depending on Differentiation, Antigen-Specificity and Anatomical Localization
Extended Co-Expression of Inhibitory Receptors by Human CD8 T-Cells Depending on Differentiation, Antigen-Specificity and Anatomical Localization
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DOI：
10.1371/journal.pone.0030852
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发表时间：
2012-02-08
期刊：
影响因子：
3.7
通讯作者：
Speiser, Daniel E.
中科院分区：
文献类型：
--
作者：
Baitsch, Lukas;Legat, Amandine;Speiser, Daniel E.
抑制性受体介导CD 8 T细胞对癌症和传染病的低反应性。PD-1和CTLA-4已经被广泛研究，阻断抗体已经显示出对癌症患者的临床益处。目前对抑制性受体及其配体的广泛共表达知之甚少。在这里，我们分析了肿瘤抗原特异性CD 8 T细胞的8种抑制性受体的表达。我们发现大多数效应T细胞同时表达四种或更多种抑制性受体BTLA、TIM-3、LAG-3、KRLG-1、2B 4、CD 160、PD-1和CTLA-4。主要差异取决于T细胞的抗原特异性、分化和解剖定位。另一方面，初始T细胞仅对BTLA和TIM-3呈单阳性或双阳性。延长的共表达可能与效应T细胞相关，因为我们发现黑色素瘤患者的转移性病变中有多种配体的表达。总之，我们的数据表明，幼稚T细胞主要由BTLA和TIM-3调节，而效应细胞通过大量的抑制性受体相互作用。同时或依次阻断多种抑制性受体可能会改善基于T细胞的治疗，但需要进一步研究以阐明每个受体-配体对的作用。
Inhibitory receptors mediate CD8 T-cell hyporesponsiveness against cancer and infectious diseases. PD-1 and CTLA-4 have been extensively studied, and blocking antibodies have already shown clinical benefit for cancer patients. Only little is known on extended co-expression of inhibitory receptors and their ligands. Here we analyzed the expression of eight inhibitory receptors by tumor-antigen specific CD8 T-cells. We found that the majority of effector T-cells simultaneously expressed four or more of the inhibitory receptors BTLA, TIM-3, LAG-3, KRLG-1, 2B4, CD160, PD-1 and CTLA-4. There were major differences depending on antigen-specificity, differentiation and anatomical localization of T-cells. On the other hand, naive T-cells were only single or double positive for BTLA and TIM-3. Extended co-expression is likely relevant for effector T-cells, as we found expression of multiple ligands in metastatic lesions of melanoma patients. Together, our data suggest that naive T-cells are primarily regulated by BTLA and TIM-3, whereas effector cells interact via larger numbers of inhibitory receptors. Blocking multiple inhibitory receptors simultaneously or sequentially may improve T-cell based therapies, but further studies are necessary to clarify the role of each receptor-ligand pair.