Department of Hematology and.
Blood. 2014 Jan 30;123(5):717-24. doi: 10.1182/blood-2013-08-518183. Epub 2013 Nov 18.
In chronic lymphocytic leukemia (CLL), CD8(+) T cells exhibit features of exhaustion and impaired functionality. Yet, reactivations of latent viruses such as cytomegalovirus (CMV) are uncommon in untreated CLL, suggesting that antiviral responses are uncompromised. We analyzed phenotypical and functional characteristics of CMV-specific CD8(+) T cells in CLL patients in comparison with age-matched healthy controls (HCs). Despite increased expression of the inhibitory receptors PD1, CD160, and CD244 on total CD8(+) T cells in CLL, expression levels of these markers were decreased on CMV-tetramer(+)CD8(+) T cells. Second, cytokine production upon stimulation with both phorbol 12-myristate 13-acetate/ionomycin and CMV-peptide-loaded antigen-presenting cells was intact in CMV-tetramer(+)CD8(+) T cells. Third, CMV-tetramer(+)CD8(+) T cells of CLL patients and HCs were equally effective in killing CMV-peptide-loaded target cells. Finally, quantitative imaging flow cytometry revealed that the proportion of CD8(+) T cells forming immunologic synapses with CMV-peptide-loaded B cells was intact. In conclusion, despite evidence for global T-cell dysfunction in CLL, we show here that CLL-derived CMV-specific CD8(+) T cells display lower expression of exhaustion markers and are functionally intact. These data indicate that the changes in the T-cell compartment in CLL may be more heterogeneous than presently assumed.
在慢性淋巴细胞白血病 (CLL) 中，CD8(+) T 细胞表现出衰竭和功能受损的特征。然而，未经治疗的 CLL 中很少发生潜伏病毒（如巨细胞病毒 [CMV]）的再激活，这表明抗病毒反应没有受到损害。我们分析了 CLL 患者与年龄匹配的健康对照者 (HC) 中 CMV 特异性 CD8(+) T 细胞的表型和功能特征。尽管 CLL 中总 CD8(+) T 细胞上抑制性受体 PD1、CD160 和 CD244 的表达增加，但 CMV-四聚体 (+) CD8(+) T 细胞上这些标志物的表达水平降低。其次，在用佛波醇 12-肉豆蔻酸 13-乙酸盐/离子霉素和 CMV 肽负载的抗原呈递细胞刺激后，CMV-四聚体 (+) CD8(+) T 细胞中的细胞因子产生完整。第三，CLL 患者和 HCs 的 CMV-四聚体 (+) CD8(+) T 细胞在杀伤 CMV 肽负载的靶细胞方面同样有效。最后，定量成像流式细胞术显示，与 CMV 肽负载 B 细胞形成免疫突触的 CD8(+) T 细胞的比例完整。总之，尽管 CLL 中存在整体 T 细胞功能障碍的证据，但我们在这里表明，CLL 衍生的 CMV 特异性 CD8(+) T 细胞表现出较低的衰竭标志物表达水平，并且功能完整。这些数据表明，CLL 中 T 细胞区室的变化可能比目前假设的更为异质。
