Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eμ-TCL1 CLL mouse model
Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eμ-TCL1 CLL mouse model
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DOI：
10.1182/blood-2015-02-626754
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发表时间：
2015-07-09
期刊：
影响因子：
20.3
通讯作者：
Gribben, John G.
中科院分区：
文献类型：
--
作者：
McClanahan, Fabienne;Riches, John C.;Gribben, John G.
T细胞缺陷、免疫抑制和抗肿瘤免疫应答差是慢性淋巴细胞白血病（CLL）的标志，PD-1/PD-L1抑制性信号传导已成为主要的免疫抑制机制。然而，不同微环境的影响和老化的混杂影响知之甚少。目前的研究使用复制人类T细胞缺陷的E mu-TCL 1小鼠模型作为临床前平台，纵向检查T细胞功能障碍的模式以及发展中的CLL和不同的微环境，重点是PD-1/PD-L1相互作用。CLL的发生与所有器官和功能的T细胞表型变化显着相关。虽然部分反映在老化的野生型小鼠，CLL特异性T细胞的变化进行了鉴定。小鼠CLL细胞在所有器官中高度表达PD-L1和PD-L2，在脾脏中高度表达PD-L1。来自白血病和衰老健康小鼠的CD 3（+）CD 8（+）T细胞高度表达PD-1，将衰老确定为混杂因素，但过继转移实验证明了CLL特异性PD-1诱导。对衰老的CLL小鼠和对照小鼠之间的PD-1表达和功能的直接比较将CLL中的PD-1（+）T细胞鉴定为具有可变效应器功能的异质群体。这与CD 8（+）T细胞的治疗靶向高度相关，显示了重编程和选择性亚群扩增以恢复抗肿瘤免疫的潜力。
T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the E mu-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3(+)CD8(+) T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1(+) T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8(+) T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity.