Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo
Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo
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DOI：
10.1182/blood-2005-07-2834
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发表时间：
2006-02-01
期刊：
影响因子：
20.3
通讯作者：
Biron, CA
中科院分区：
文献类型：
--
作者：
Gil, MP;Salomon, R;Biron, CA
1型干扰素（IFN）在体内被诱导、治疗性施用，并且是改善自身免疫性疾病的潜在靶点。细胞因子介导深刻的抗增殖作用。信号转导和转录激活因子1（STAT1）依赖性信号传导途径是抑制增殖所必需的，病毒感染可引起高水平的1型IFN以及总STAT1蛋白表达。因此，必须有一种机制来帮助抗原特异性T细胞克服IFN诱导的增殖抑制。这里报道的研究表明，总的CD8 T细胞增殖IFN的存在下，离体响应于细胞因子和在体内病毒感染期间，通过STAT1依赖性机制抑制。相比之下，在病毒攻击后的关键时间，抗原特异性CD8 T细胞而不是CD4 T细胞的主要比例对这种抑制不太敏感，表达较低的内源性总STAT 1水平，并且在1型IFN中选择性增殖。总之，这些新的结果表明，差异STAT1的表达是由免疫系统来修改对T细胞扩增的精氨酸介导的影响，并有影响的细胞因子功能的治疗干预的后果。
Type 1 interferons (IFNs) are induced in vivo, administered therapeutically, and potential targets for amelioration of autoimmune diseases. The cytokines mediate profound antiproliferative effects. Signal transducer and activator of transcription 1 (STAT1)-dependent signaling pathways are required for inhibition of proliferation, and viral infections can elicit high levels of type 1 IFNs as well as total STAT1 protein expression. Thus, a mechanism must be in place to help antigen-specific T cells overcome IFN-induced inhibition of proliferation. The studies reported here demonstrate that total CD8 T-cell proliferation in the presence of IFNs, ex vivo in response to cytokines and in vivo during viral infection, is inhibited through a STAT1-dependent mechanism. In contrast, major proportions of antigen-specific CD8, but not CD4, T cells are rendered less sensitive to this inhibition, express lower endogenous levels of total STAT1, and are selectively proliferating in the of type 1 IFN, at key times after viral challenge. Taken together, these novel results show that differential STAT1 expression is used by the immune system to modify cytokine-mediated effects on T-cell expansion and have implications for the consequences of therapeutic intervention in cytokine function.