Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy.
Laboratory of Neuroembriology, Fondazione Santa Lucia, Rome, Italy.
Cell Death Differ. 2019 Jun;26(6):1169-1180. doi: 10.1038/s41418-018-0201-9. Epub 2018 Sep 26.
Polarization of naive T cells into interferon (IFN)-γ-producing T helper 1 (Th1) cells is an essential event in the inflammatory response to pathogens. Herein, we identify the RNA binding protein Sam68 as a specific modulator of Th1 differentiation. Sam68-knockout (ko) naive T cells are strongly defective in IL-12-mediated Th1 polarization and express low levels of T-bet and Eomes. Consequently, Sam68-ko Th1 cells are significantly impaired in IFN-γ production. Moreover, we found that Sam68 is required for the induction of an inflammatory Th1 response during Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, thus limiting bacterial dissemination in the lungs. Mechanistically, Sam68 directly binds to the microRNA miR-29, a negative regulator of Th1 response, and inhibits its expression during BCG infection. These findings uncover a novel post-transcriptional mechanism required for the Th1-mediated defense against intracellular pathogens and identify a new function for Sam68 in the regulation of the immune response.
幼稚 T 细胞向产生干扰素 (IFN)-γ的辅助性 T 细胞 1（Th1）的极化是对病原体发生炎症反应的一个必要事件。在此，我们确定 RNA 结合蛋白 Sam68 是 Th1 分化的一个特定调节因子。Sam68 敲除（ko）幼稚 T 细胞在 IL-12 介导的 Th1 极化中严重缺陷，并表达低水平的 T-bet 和 Eomes。因此，Sam68-ko Th1 细胞在 IFN-γ产生方面显著受损。此外，我们发现 Sam68 在感染牛分枝杆菌卡介苗（BCG）期间诱导炎症性 Th1 反应是必需的，从而限制了肺部的细菌传播。在机制上，Sam68 直接与 microRNA miR-29 结合，miR-29 是 Th1 反应的负调节因子，并在 BCG 感染期间抑制其表达。这些发现揭示了一种新的、针对细胞内病原体的 Th1 介导防御所必需的转录后机制，并确定了 Sam68 在调节免疫反应中的新功能。
