Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection
Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection
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DOI：
10.4049/jimmunol.1402607
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发表时间：
2015-09-01
影响因子：
4.4
通讯作者：
Schachtrup, Kristina
中科院分区：
文献类型：
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作者：
Menner, Alexandra J.;Rauch, Katharina S.;Schachtrup, Kristina
慢性感染中持续存在的Ag会导致CD8(+) T细胞反应失调，其特征是T细胞耗竭和Ag特异性CD8(+) T细胞的细胞死亡。然而，调节 CD8(+) T 细胞耗竭和细胞死亡的潜在转录机制尚不清楚。利用淋巴细胞性脉络膜脑膜炎病毒感染的实验小鼠模型，我们证明转录调节因子Id3控制慢性感染中病毒特异性CD8+T细胞的细胞死亡。通过比较急性和慢性感染，我们发现在慢性和急性感染中，Id36(-)病毒特异性CD8(+)T细胞的丰度较低，而Id3(+)病毒特异性CD8(+)T细胞的绝对数量相等。表型上，Id3- 和 Id3(+) 细胞在表面受体 2B4 的表达方面存在最显着的差异。尽管Id3(-)细胞为2B4(+)，但几乎所有Id3(+)细胞均缺乏2B4的表达。谱系追踪实验表明，最初表达Id3的细胞分化为Id3(-)2B4(+)细胞；反过来，这些细胞是终末分化的，并且在持续存在Ag的条件下高度容易发生细胞死亡。强制Id3表达通过降低对Fas/Fas配体介导的细胞死亡的敏感性，特异性地增加2B4(+)病毒特异性CD8(+)T细胞的持久性。因此，我们的研究结果表明，转录调节因子Id3促进慢性感染中病毒特异性CD8+T细胞的存活，并表明靶向Id3可能有益于预防慢性感染中CD8+T细胞的细胞死亡，或促进不受控制的、过度活跃的CD8+T细胞的细胞死亡以预防免疫病理学。
Sustained Ag persistence in chronic infection results in a deregulated CD8(+) T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8(+) T cells. Yet, the underlying transcriptional mechanisms regulating CD8(+) T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8(+) T cells in chronic infection. By comparing acute and chronic infection, we showed that Id36(-) virus-specific CD8(+) T cells were less abundant, whereas the absolute numbers of Id3(+) virus-specific CD8(+) T cells were equal in chronic and acute infection. Phenotypically, Id3- and Id3(+) cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3(-) cells were 2B4(+), almost all Id3(+) cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3(-)2B4(+) cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4(+) virus-specific CD8(+) T cells by decreasing susceptibility to Fas/Fas ligand-mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8(+) T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8(+) T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8(+) T cells to prevent immunopathology.