本期文章：《细胞》：Online/在线发表

近日，法国国家健康与医学研究院Jean-Laurent Casanova等研究人员合作发现，人类MCTS1依赖的JAK2翻译对分枝杆菌的IFN-γ免疫至关重要。2023年10月23日，《细胞》杂志在线发表了这项成果。

研究人员报告了来自不同血统（中国、芬兰、伊朗和沙特阿拉伯）的男性霉菌病患者中的X连锁隐性MCTS1缺乏症。这种翻译再启动因子的完全缺乏会影响一些蛋白质的翻译，包括所有测试细胞类型（包括T淋巴细胞和吞噬细胞）中激酶JAK2的翻译。JAK2的表达量低到足以影响细胞对白细胞介素-23（IL-23）的反应，部分影响IL-12，但不影响其他依赖JAK2的细胞因子。对IL-23的反应缺陷会优先损害先天类适应性粘膜相关不变T细胞（MAIT）和γδ T淋巴细胞在受到分枝杆菌挑战时产生的干扰素-γ（IFN-γ）。令人惊讶的是，在这些患者中，缺乏MCTS1依赖性翻译再启动和核糖体再循环似乎在生理上是多余的。

这些研究结果表明，X连锁隐性人类MCTS1缺乏症通过损害先天类适应性T淋巴细胞中的JAK2翻译，从而损害IL-23依赖性诱导的IFN-γ，这是孤立性霉菌病的基础。

研究人员表示，人类IFN-γ免疫功能的遗传性紊乱是严重的分枝杆菌病的基础。

附：英文原文

Title: Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria

Author: Jonathan Bohlen, Qinhua Zhou, Quentin Philippot, Masato Ogishi, Darawan Rinchai, Tea Nieminen, Simin Seyedpour, Nima Parvaneh, Nima Rezaei, Niloufar Yazdanpanah, Mana Momenilandi, Clément Conil, Anna-Lena Neehus, Carltin Schmidt, Carlos A. Arango-Franco, Tom Le Voyer, Taushif Khan, Rui Yang, Julia Puchan, Lucia Erazo, Mykola Roiuk, Taja Vatovec, Zarah Janda, Ivan Bagari, Marie Materna, Adrian Gervais, Hailun Li, Jérémie Rosain, Jessica N Peel, Yoann Seeleuthner, Ji Eun Han, Anne-Sophie L’Honneur, Marcela Moncada-Vélez, Marta Martin-Fernandez, Michael E. Horesh, Tatiana Kochetkov, Monika Schmidt, Mohammed A. AlShehri, Eeva Salo, Harri Saxen, Gehad ElGhazali, Ahmad Yatim, Camille Soudée, Federica Sallusto, Armin Ensser, Nico Marr, Peng Zhang, Dusan Bogunovic, Aurélie Cobat, Mohammad Shahrooei

Issue&Volume: 2023-10-23

Abstract: Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

DOI: 10.1016/j.cell.2023.09.024