Proliferation Capacity and Cytotoxic Activity Are Mediated by Functionally and Phenotypically Distinct Virus-Specific CD8 T Cells Defined by Interleukin-7Rα (CD127) and Perforin Expression
Proliferation Capacity and Cytotoxic Activity Are Mediated by Functionally and Phenotypically Distinct Virus-Specific CD8 T Cells Defined by Interleukin-7Rα (CD127) and Perforin Expression
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DOI：
10.1128/jvi.02565-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Harari, Alexandre
中科院分区：
文献类型：
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作者：
Cellerai, Cristina;Perreau, Matthieu;Harari, Alexandre
细胞毒性和增殖能力是抗病毒CD 8 T细胞的关键功能。在本研究中，我们研究了一系列标志物来定义病毒特异性CD 8 T细胞中的这些功能。我们提供的证据表明，在人CD 8 T细胞中缺乏穿孔素和CD 127的共表达。病毒特异性CD 8 T细胞上的CD 127表达与增殖能力呈正相关，与穿孔素表达和细胞毒性呈负相关。流感病毒、巨细胞病毒和EB病毒/人类免疫缺陷病毒1型特异性CD 8 T细胞主要分别由CD 127（+）穿孔素（-）/CD 127（-）穿孔素（+）和CD 127（-）/穿孔素（-）CD 8 T细胞组成。CD 127（-）/perforin（-）和CD 127（-）/perforin（+）细胞分别表达显著更多的PD-1和CD 57。一致地，细胞内细胞因子（γ干扰素、肿瘤坏死因子α和白细胞介素-2 [IL-2]）应答结合穿孔素检测证实病毒特异性CD 8 T细胞主要由穿孔素（+）/IL-2（-）或穿孔素（-）/IL-2（+）细胞组成。病毒特异性CD 8 T细胞中穿孔素表达与IL-2分泌呈负相关（P < 0.01）。如前所示，穿孔素，抗原暴露的变化也调制CD 127的表达。基于上述结果，增殖性（分泌CD 127（+）/IL-2）和细胞毒性（穿孔素（+））CD 8 T细胞包含在处于不同活化或分化阶段的表型不同的T细胞群中，并显示出不同水平的耗竭和衰老。此外，对于给定的抗病毒CD 8 T细胞群体，增殖和细胞毒性CD 8 T细胞的组成似乎受到抗原暴露的影响。这些结果推进了我们对抗病毒记忆性CD 8 T细胞的细胞毒性、增殖能力、衰老和衰竭水平以及抗原暴露之间关系的理解。
Cytotoxicity and proliferation capacity are key functions of antiviral CD8 T cells. In the present study, we investigated a series of markers to define these functions in virus-specific CD8 T cells. We provide evidence that there is a lack of coexpression of perforin and CD127 in human CD8 T cells. CD127 expression on virus-specific CD8 T cells correlated positively with proliferation capacity and negatively with perforin expression and cytotoxicity. Influenza virus-, cytomegalovirus-, and Epstein-Barr virus/human immunodeficiency virus type 1-specific CD8 T cells were predominantly composed of CD127(+) perforin(-)/CD127(-) perforin(+), and CD127(-)/perforin(-) CD8 T cells, respectively. CD127(-)/perforin(-) and CD127(-)/perforin(+) cells expressed significantly more PD-1 and CD57, respectively. Consistently, intracellular cytokine (gamma interferon, tumor necrosis factor alpha, and interleukin-2 [IL-2]) responses combined to perforin detection confirmed that virus-specific CD8 T cells were mostly composed of either perforin (+)/IL-2(-) or perforin(-)/IL-2(+) cells. In addition, perforin expression and IL-2 secretion were negatively correlated in virus-specific CD8 T cells (P < 0.01). As previously shown for perforin, changes in antigen exposure modulated also CD127 expression. Based on the above results, proliferating (CD127(+)/IL-2-secreting) and cytotoxic (perforin(+)) CD8 T cells were contained within phenotypically distinct T-cell populations at different stages of activation or differentiation and showed different levels of exhaustion and senescence. Furthermore, the composition of proliferating and cytotoxic CD8 T cells for a given antiviral CD8 T-cell population appeared to be influenced by antigen exposure. These results advance our understanding of the relationship between cytotoxicity, proliferation capacity, the levels of senescence and exhaustion, and antigen exposure of antiviral memory CD8 T cells.