ID2 and ID3 are indispensable for Th1 cell differentiation during influenza virus infection in mice
ID2 and ID3 are indispensable for Th1 cell differentiation during influenza virus infection in mice
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ID2和ID3对于小鼠流感病毒感染过程中Th1细胞分化是必不可少的
DOI：
10.1002/eji.201847822
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发表时间：
2019-03-01
影响因子：
5.4
通讯作者：
Zhang, Fuping
中科院分区：
文献类型：
--
作者：
Han, Xiaojuan;Liu, Hongtao;Zhang, Fuping
抗原特异性Th1细胞可以在感染过程中传代至感染部位以执行效应器功能，例如通过分泌抗病毒细胞因子IFN-γ或直接杀伤抗原携带细胞来帮助CD8（+）T细胞定位于这些部位。然而，调节Th1细胞分化和功能的分子组分对病毒感染的反应仍不完全清楚。本文报道了DNA结合抑制因子3（Inhibitor of DNA binding 3，Id3）和DNA结合抑制因子2（Inhibitor of DNA binding 2，Id2）蛋白均能促进Th1细胞的分化。流感病毒感染时Id3或Id2缺失导致Th1细胞分化严重缺陷。而在CD4（+）T细胞中Id3和Id2的耗竭在更大程度上抑制Th1细胞分化，表明Id3和Id2非冗余地调节Th1细胞分化。此外，删除Id蛋白的拮抗剂E蛋白，大大增强了Th1细胞的分化。机制研究表明，E蛋白通过直接与Th1细胞主调节因子T-bet的调节元件结合，调节T-bet的表达，从而抑制Th1细胞的分化。因此，我们的研究结果确定了Id蛋白的重要性，为Th1细胞的分化，并澄清了非冗余的作用，Id3和Id2调节Th1细胞分化，提供了新的见解，Id3-Id2-E蛋白轴是必不可少的Th1细胞极化。
Antigen-specific Th1 cells could be a passage to the infection sites during infection to execute effector functions, such as help CD8(+) T cells to localize in these sites by secretion of anti-viral cytokines-IFN-gamma or direct cytotoxicity of antigen-bearing cells. However, the molecular components that modulate Th1 cell differentiation and function in response to viral infection remain incompletely understood. Here, we reported that both inhibitor of DNA binding 3(Id3) protein and inhibitor of DNA binding 2(Id2) protein promoted Th1 cell differentiation. Depletion of Id3 or Id2 led to severe defect of Th1 cell differentiation during influenza virus infection. Whereas depletion of both Id3 and Id2 in CD4(+) T cells restrained Th1 cell differentiation to a greater extent, indicating that Id3 and Id2 nonredundantly regulate Th1 cell differentiation. Moreover, deletion of E-proteins, the antagonists of Id proteins, greatly enhanced Th1 cell differentiation. Mechanistic study indicated that E-proteins suppressed Th1 cell differentiation by directly binding to the regulatory elements of Th1 cell master regulator T-bet and regulate T-bet expression. Thus, our findings identified Id-protein's importance for Th1 cells and clarified the nonredundant role of Id3 and Id2 in regulating Th1 cell differentiation, providing novel insight that Id3-Id2-E protein axis are essential for Th1 cell polarization.