Kamimura Daisuke, Atsumi Toru, Stofkova Andrea, Nishikawa Naoki, Ohki Takuto, Suzuki Hironao, Katsunuma Kokichi, Jiang Jing-Jing, Bando Hidenori, Meng Jie, Sabharwal Lavannya, Ogura Hideki, Hirano Toshio, Arima Yasunobu, Murakami Masaaki
Division of Molecular Neuroimmunology, Institute for Genomic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Laboratory of Developmental Immunology, WPI Immunology Frontier Research Center, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; Laboratory of Developmental Immunology, WPI Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Suita, Japan.
Division of Molecular Neuroimmunology, Institute for Genomic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo , Japan.
Front Immunol. 2015 Dec 17;6:638. doi: 10.3389/fimmu.2015.00638. eCollection 2015.
The survival of naïve T cells is believed to require signals from TCR-pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naïve T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naïve T cells (T-Red mice). T-Red mice have a point mutation in the Kdelr1 gene, and their naïve T cells show enhanced integrated stress response (ISR), which eventually induces their apoptosis. Therefore, naïve T cells require a KDEL receptor-mediated mechanism that efficiently relieves cellular stress for their survival in vivo. Interestingly, naïve T cells expressing TCR with higher affinity/avidity to self-antigens survive in T-Red mice, suggesting the possible link between TCR-mediated survival and ISR-induced apoptosis. In this article, we discuss the regulation of naïve T cell homeostasis, keeping special attention on the ISR and TCR signal.
幼稚T细胞的存活被认为需要来自TCR-pMHC相互作用的信号以及诸如白细胞介素-7等细胞因子。相比之下，对幼稚T细胞存活产生负面影响的信号则了解较少。我们对小鼠进行了正向遗传学筛选，发现了一种幼稚T细胞数量减少的突变小鼠品系（T-Red小鼠）。T-Red小鼠的Kdelr1基因存在一个点突变，其幼稚T细胞表现出增强的综合应激反应（ISR），最终诱导其凋亡。因此，幼稚T细胞需要一种KDEL受体介导的机制来有效缓解细胞应激，以实现其在体内的存活。有趣的是，表达对自身抗原有更高亲和力/亲合力的TCR的幼稚T细胞能在T-Red小鼠中存活，这表明TCR介导的存活与ISR诱导的凋亡之间可能存在联系。在本文中，我们讨论了幼稚T细胞稳态的调节，特别关注ISR和TCR信号。
