The tRNA pool determines the efficiency, throughput, and accuracy of translation. Previous studies have identified dynamic changes in the tRNA (transfer RNA) supply and mRNA (messenger RNA) demand during cancerous proliferation. Yet dynamic changes may also occur during physiologically normal proliferation, and these are less well characterized. We examined the tRNA and mRNA pools of T cells during their vigorous proliferation and differentiation upon triggering their antigen receptor. We observed a global signature of switch in demand for codons at the early proliferation phase of the response, accompanied by corresponding changes in tRNA expression levels. In the later phase, upon differentiation, the response of the tRNA pool relaxed back to the basal level, potentially restraining excessive proliferation. Sequencing of tRNAs allowed us to evaluate their diverse base-modifications. We found that two types of tRNA modifications, wybutosine and ms²t6A, are reduced dramatically during T cell activation. These modifications occur in the anticodon loops of two tRNAs that decode “slippery codons,” which are prone to ribosomal frameshifting. Attenuation of these frameshift-protective modifications is expected to increase the potential for proteome-wide frameshifting during T cell proliferation. Indeed, human cell lines deleted of a wybutosine writer showed increased ribosomal frameshifting, as detected with an HIV gag-pol frameshifting site reporter. These results may explain HIV’s specific tropism toward proliferating T cells since it requires ribosomal frameshift exactly on the corresponding codon for infection. The changes in tRNA expression and modifications uncover a layer of translation regulation during T cell proliferation and expose a potential tradeoff between cellular growth and translation fidelity.

tRNA 池决定了翻译的效率、吞吐量和准确性。以前的研究已经确定了癌症增殖过程中 tRNA（转移 RNA）供应和 mRNA（信使 RNA）需求的动态变化。然而，在生理正常的增殖过程中也可能发生动态变化，并且这些变化不太清楚。我们检查了 T 细胞在触发其抗原受体后的剧烈增殖和分化过程中的 tRNA 和 mRNA 池。我们观察到在反应的早期增殖阶段对密码子的需求转换的全球特征，伴随着 tRNA 表达水平的相应变化。在后期，分化后，tRNA 池的反应放松到基础水平，可能抑制过度增殖。tRNA 的测序使我们能够评估它们不同的碱基修饰。我们发现两种类型的 tRNA 修饰，wybutosine 和 ms²t6A 在 T 细胞活化期间显着降低。这些修饰发生在两个 tRNA 的反密码子环中，这些 tRNA 解码容易发生核糖体移码的“滑密码子”。预计这些移码保护性修饰的减弱会增加 T 细胞增殖过程中蛋白质组范围内移码的潜力。事实上，删除 wybutosine writer 的人类细胞系显示核糖体移码增加，正如 HIV gag-pol 移码位点报告基因所检测到的那样。这些结果可能解释了 HIV 对增殖 T 细胞的特定嗜性，因为它需要核糖体移码恰好在相应的密码子上才能感染。