Hwang SS, Lim J, Yu Z, Kong P, Sefik E, Xu H, Harman CCD, Kim LK, Lee GR, Li HB, Flavell RA.
T cells maintain a quiescent state prior to activation. As inappropriate T cell activation can cause disease, T cell quiescence must be preserved. Despite its importance, the mechanisms underlying the “quiescent state” remain elusive. Here, we identify BTG1 and BTG2 (BTG1/2) as factors responsible for T cell quiescence. BTG1/2-deficient T cells show an increased proliferation and spontaneous activation due to a global increase in messenger RNA (mRNA) abundance, which reduces the threshold to activation. BTG1/2 deficiency leads to an increase in polyadenylate tail length, resulting in a greater mRNA half-life. Thus, BTG1/2 promote the deadenylation and degradation of mRNA to secure T cell quiescence. Our study reveals a key mechanism underlying T cell quiescence and suggests that low mRNA abundance is a crucial feature for maintaining quiescence.
In conclusion, we propose a model to explain how the quiescent state in T cells is maintained (Fig. 4G). BTG1 and BTG2 are highly and specifically expressed in quiescent T cells and promotemRNA deadenylation and degradation. Unlike BTG1/2, deadenylases appear to be ubiquitously expressed at a low level, implying a specialized function of BTG1/2 in immune cells (fig. S17). Because BTG1/2 interact with PABP and the CNOT complex, which bind nonspecifically to mRNAs (25), BTG1/2 can direct the down-regulation of mRNAs at a global level. This mechanism is seemingly inefficient in terms of cost, but the availability of presynthesized mRNA provides a benefit to quiescent T cells of a rapid response to activation signals. Given that naïve T cells differentiate into multiple lineages, having such a primed state on a hair trigger would be ultimately beneficial. Upon activation, BTG1/2 quickly disappear, which results in an accumulation of mRNAs and exit from the quiescent state (Figs. 1D and 4G).