mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence [mTAIL-seq]

Quiescence is a cellular state in which cells undergo reversible cell cycle arrest in response to environmental challenges or lack of stimuli. When favourable conditions are engaged, the cells exit quiescence and start to proliferate. For example, quiescent stem cells and oocytes are activated by differentiation signals and fertilization, respectively. The regulation of quiescent state is also crucial for lymphocytes, such as T cells. Inappropriate activation of T cells often leads to autoimmune diseases and thus, the balance between quiescent and activated T cells must be preserved. Despite its importance, however, how T cells maintain the ‘quiescent state’ and exit from it remain largely unknown. Here, we identify BTG1 and BTG2 (BTG1/2) as factors responsible for T cell quiescence. Knockout of Btg1/2 in T cells resulted in a reduced threshold to T cell activation, increased proliferation and a concomitant reduction of the frequency of naive T cells. Loss of BTG1/2 rendered naive T cells to become spontaneously activated even without TCR stimuli. Interestingly, we found a global increase in mRNA abundance in naive T cells that lack BTG1/2. In addition, depletion of BTG1/2 led to an increase in mRNA half-life and poly(A) tail length. Thus, BTG1/2 promotes deadenylation and degradation of mRNA in naive T cells. Our study demonstrates a key mechanism underlying T cell quiescence, and suggests low mRNA abundance as a key feature for maintaining quiescent T cells. Three replicates of naive CD4 T cells (TCRb+CD4+CD25-CD62LhiCD44low) from WT and DKO mice, respectively.

静息态（Quiescence）是一类细胞状态，指细胞在遭遇环境胁迫或缺乏刺激信号时，会发生可逆的细胞周期阻滞。当有利条件出现时，细胞将退出静息态并开始增殖。例如，静息态干细胞与卵母细胞分别可通过分化信号与受精作用被激活。静息态的调控对于淋巴细胞（如T细胞）同样至关重要。T细胞的异常活化常引发自身免疫疾病，因此必须维持静息态与活化态T细胞之间的动态平衡。尽管其重要性不言而喻，但目前学界对T细胞如何维持静息态以及退出静息态的具体机制仍知之甚少。本研究鉴定出BTG1与BTG2（BTG1/2）为调控T细胞静息态的关键因子。在T细胞中敲除Btg1/2会降低T细胞的活化阈值、增强其增殖能力，并伴随初始T细胞（naive T cells）频率的显著下降。BTG1/2的缺失会使初始T细胞即使在无T细胞受体（TCR）刺激的情况下也会发生自发活化。值得注意的是，本研究发现BTG1/2缺失的初始T细胞中，mRNA的整体丰度显著升高。此外，BTG1/2的敲除会延长mRNA的半衰期与poly(A)尾长度。由此可见，BTG1/2可促进初始T细胞内mRNA的脱腺苷酸化与降解过程。本研究揭示了T细胞静息态维持的关键机制，并提出mRNA低丰度是维持静息态T细胞的核心特征之一。本研究分别从野生型（WT）与双基因敲除（DKO）小鼠中采集了初始CD4 T细胞（TCRb+CD4+CD25-CD62LhiCD44low），每组设置三次生物学重复。