The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes.
The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes.
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DOI：
10.7554/elife.30496
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发表时间：
2018-02-28
期刊：
影响因子：
7.7
通讯作者：
Marchant A
中科院分区：
文献类型：
--
作者：
Serroukh Y;Gu-Trantien C;Hooshiar Kashani B;Defrance M;Vu Manh TP;Azouz A;Detavernier A;Hoyois A;Das J;Bizet M;Pollet E;Tabbuso T;Calonne E;van Gisbergen K;Dalod M;Fuks F;Goriely S;Marchant A
细胞毒性 CD4 (CD4CTX) T 细胞正在成为抗病毒和抗肿瘤免疫的重要组成部分，但其发育的分子基础仍知之甚少。在人类巨细胞病毒感染的情况下，很大一部分 CD4 T 细胞表现出细胞毒功能。我们观察到，尽管不存在 ThPOK 下调，但这些细胞的转录程序富含 CD8 T 细胞谱系基因。我们进一步表明，CD4CTX 特异性转录和表观遗传程序的建立是沿着 Th1 分化途径逐步发生的。在体外，在 Th1 极化细胞因子存在下，幼稚 CD4 T 细胞的长时间激活导致获得穿孔素依赖性细胞毒活性。该过程依赖于 Th1 转录因子 Runx3，并受到 ThPOK 持续表达的限制。这项工作阐明了人类 CD4CTX T 细胞的分子程序，并确定了针对病毒感染和癌症的免疫疗法的潜在靶点。
Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.