Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses.
Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses.
复制标题
DOI：
10.4049/jimmunol.1500218
复制
发表时间：
2016-02-01
期刊：
影响因子：
--
通讯作者：
Ford ML
中科院分区：
文献类型：
--
作者：
Liu D;Burd EM;Coopersmith CM;Ford ML
T 细胞遇到抗原后，多个信号被整合，共同诱导抗原特异性 CD8+ T 细胞群内不同的分化程序。有几个因素影响这些细胞命运的决定，包括抗原的数量和持续时间、炎症细胞因子的暴露以及共信号分子的连接程度。诱导型共刺激因子 (ICOS) 不在静息 T 细胞上表达，但在遇到抗原时迅速上调。然而，ICOS 信号传导对程序性分化的影响尚不清楚。因此，在本研究中，我们试图确定 ICOS 信号传导对 CD8+ T 细胞程序性分化的作用。通过创建新型 ICOS 逆转录抗原特异性 TCR 转基因 CD8+ T 细胞，我们研究了在抗原暴露期间接收早期和持续的 ICOS 信号的 CD8+ T 细胞的表型、功能和记忆潜力。我们的结果表明，与空载体对照相比，这些 ICOS 信号严重影响抗原特异性 CD8+ T 细胞的细胞命运决定，导致 KLRG-1hiCD127lo 细胞频率增加，BLIMP-1、T-bet 和脱中胚蛋白表达改变，并增加细胞溶解能力。然而有趣的是，ICOS 逆转录 CD8+ T 细胞也优先归巢于非淋巴器官，并表现出多细胞因子功能降低和体内挑战时发起二次回忆反应的能力降低。总之，我们的结果表明，在早期和持续的ICOS表达后，诱导了分化程序的改变，导致产生更具细胞溶解能力的终末分化效应子，其记忆反应能力有限。
Following T cell encounter with antigen, multiple signals are integrated to collectively induce distinct differentiation programs within antigen-specific CD8+ T cell populations. Several factors contribute to these cell fate decisions including the amount and duration of antigen, exposure to inflammatory cytokines, and degree of ligation of cosignaling molecules. The inducible costimulator (ICOS) is not expressed on resting T cells but is rapidly upregulated upon encounter with antigen. However, the impact of ICOS signaling on programmed differentiation is not well understood. In this study we therefore sought to determine the role of ICOS signaling on CD8+ T cell programmed differentiation. Through the creation of novel ICOS retrogenic antigen-specific TCR transgenic CD8+ T cells, we interrogated the phenotype, functionality, and recall potential of CD8+ T cells that receive early and sustained ICOS signaling during antigen exposure. Our results reveal that these ICOS signals critically impacted cell fate decisions of antigen-specific CD8+ T cells, resulting in increased frequencies of KLRG-1hiCD127lo cells, altered BLIMP-1, T-bet, and eomesodermin expression, and increased cytolytic capacity as compared to empty vector controls. Interestingly, however, ICOS retrogenic CD8+ T cells also preferentially homed to non-lymphoid organs, and exhibited reduced multi-cytokine functionality and reduced ability to mount secondary recall responses upon challenge in vivo. In sum, our results suggest that an altered differentiation program is induced following early and sustained ICOS expression, resulting in the generation of more cytolyticly potent, terminally differentiated effectors that possess limited capacity for recall response.