Expanded CD8+ T cells of murine and human CLL are driven into a senescent KLRG1+ effector memory phenotype
Expanded CD8+ T cells of murine and human CLL are driven into a senescent KLRG1+ effector memory phenotype
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DOI：
10.1007/s00262-013-1473-z
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发表时间：
2013-11-01
影响因子：
5.8
通讯作者：
Duerig, Jan
中科院分区：
文献类型：
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作者：
Goethert, Joachim Rudolf;Eisele, Lewin;Duerig, Jan
T细胞的数量和功能改变先前已在慢性淋巴细胞白血病（CLL）患者中得到证实。然而，动力学和特定的T细胞亚群的变化还没有被详细研究。因此，我们研究了慢性淋巴细胞白血病血液淋巴细胞亚群的个体患者在纵向的方式。血液中CD 4（+）和CD 8（+）T细胞数量的动态扩增与CLL白血病室的进行性增加一致。有趣的是，随着时间的推移，T细胞亚群的扩增在CD 38（+）CLL中更为明显。此外，我们对CLL患者和正常供体的CD 3（+）T细胞进行了基因表达谱分析。使用基因集富集分析，我们发现在CLL T细胞中具有较高表达的基因在CD 8（+）效应记忆和末端效应T细胞基因特征内显著富集。与这些数据一致，我们通过流式细胞术观察到CLL中表型CD 8（+）效应记忆T细胞的显著扩增。此外，我们观察到，在人类CLL和小鼠CLL（E mu-TCL 1模型）中，CD 8（+）效应记忆T细胞的增加是由于抑制性杀伤细胞凝集素样受体G1（KLRG 1）表达细胞亚群的扩增。此外，与正常供体对照相比，在CLL患者中检测到更高的天然KLRG 1配体E-钙粘蛋白的血浆水平。CD 8（+）T细胞内KLRG 1（+）表达的优势与系统性可溶性E-钙粘蛋白的增加可能显著促进CLL免疫功能障碍，并且可能另外代表CLL微环境的重要组成部分。
Altered numbers and functions of T cells have previously been demonstrated in chronic lymphocytic leukemia (CLL) patients. However, dynamics and specific T-cell subset alterations have not been studied in great detail. Therefore, we studied CLL blood lymphocyte subsets of individual patients in a longitudinal manner. Dynamic expansions of blood CD4 (+) and CD8 (+) T-cell numbers were consistently associated with a progressively increasing CLL leukemic compartment. Interestingly, the T-cell subset expansion over time was more pronounced in CD38 (+) CLL. Additionally, we performed gene expression profiling of CD3 (+) T cells of CLL patients and normal donors. Using gene set enrichment analysis, we found significant enrichment of genes with higher expression in CLL T cells within CD8(+) effector memory and terminal effector T-cell gene signatures. In agreement with these data, we observed a marked expansion of phenotypic CD8 (+) effector memory T cells in CLL by flow cytometry. Moreover, we observed that increments of CD8 (+) effector memory T cells in human CLL and also mouse CLL (E mu-TCL1 model) were due to an expansion of the inhibitory killer cell lectin-like receptor G1 (KLRG1) expressing cellular subset. Furthermore, higher plasma levels of the natural KLRG1 ligand E-cadherin were detected in CLL patients compared to normal donor controls. The predominance of KLRG1(+) expression within CD8(+) T cells in conjunction with increased systemic soluble E-cadherin might significantly contribute to CLL immune dysfunction and might additionally represent an important component of the CLL microenvironment.