Guardians of silence: transcriptional networks in T cell quiescence

Abstract

The maintenance of quiescence in T cells plays a pivotal role in averting undesired immune reactions and fostering immune homeostasis. Upon receiving external signals of cognate antigen and costimulatory molecules, T cells escape a quiescent state and rapidly proliferate within an exceedingly short timeframe. Nevertheless, for the majority of their lifespan, T cells remain inactive before stimulation, yet they are highly poised to future activation, implicating the presence of dynamic and intricate regulatory processes in a seemingly dormant state. While numerous extrinsic cues have been identified to induce T cell activation from a quiescence currently, intrinsic mechanisms governing T cell quiescence have received limited attention. Here we provide a comprehensive overview of multiple factors involved in T cell quiescence and their molecular mechanisms mainly in the context of transcriptional and post-transcriptional regulation. Given the intricate interplay between the control of T cell quiescence and a variety of diseases including autoimmunity, exhaustion and even tumor control, a thorough understanding of current insights into T cell quiescence affords us a valuable opportunity to advance our comprehension of T cell biology.

Fig. 1. Quiescence begins to be established in the DP thymocyte stage and completed in fully matured naive T cells.

During circulation, multiple factors contribute to the maintenance of quiescence in naive T cells. Trafficking molecules (S1P1, CD62L and CCR7) guide T cell circulation, leading T cells to encounter diverse factors involved in the maintenance of quiescence. S1P, abundant in blood, directs egress of T cells from lymphoid organs and promote the survival of quiescent T cells via its receptor S1P1. Tonic TCR stimulation occurs in lymphoid organs by the engagement of self-peptide bearing MHC molecules and facilitate T cell quiescence. High level of IL-7 in periphery also supports the survival of T cells and prevent quiescence exit through IL-7R. Intrinsic regulators programmed in quiescent T cells coordinate these extrinsic signals for optimal maintenance of quiescence. DP, CD4⁺CD8⁺ double positive; SP, CD4⁺ or CD8⁺ single positive.

Fig. 2. Molecular interactions of intrinsic regulators in the maintenance of T cell quiescence.

The summarized molecular mechanisms of intrinsic regulators in T cell quiescence. The regulation of T cell trafficking molecules (a) and IL-7R (b), suppression of T cell activation (c), cell cycling inhibition (d) and downregulation of global mRNA abundance (e). In a, FOXO1 and KLF2 induce the transcription of T cell trafficking molecules (CD62L, S1P1 and CCR7), which are essential for proper migratory function of naive and memory T cells to maintain a quiescent state. In b, FOXO1 promotes IL-7 signaling by inducing IL-7R expression. FOXP1 inhibits IL-7R expression by antagonizing FOXO1, ultimately prevents excessive IL-7R signaling. Thus, the duration of IL-7R signaling is balanced by both FOXO1 and FOXP1. In c, TCR-mediated activating signals are suppressed by FOXP1 activity. FOXP1 directly inhibits Erk and induce the transcription of Pik3ip1, an inhibitor of PI3K. The expression of genes targeted by AP-1, an important transcription factor for effector function of activated T cells, is competitively blocked by BACH2 which share same binding sites of AP-1. Also, BACH2, induced by FOXO1 inhibits Prdm1 expression. In d, FOXP1 blocks the expression of E2F, a key molecule for cell cycle progression. FOXO1 upregulates Klf2 expression, and KLF2 and TOB1 also induce CDK inhibitors, P21 and P27, which prevent cell cycling by inhibiting CDK activity. In e, the global abundance of mRNA is downregulated by BTG1/2 expressed in a quiescent T cell. BTG1/2 bind to PABP on poly(A) tail of mRNA and recruit CNOT deadenylase complex. The interaction between BTG1/2 and CNOT complex enhance deadenylase activity, resulting in mRNA degradation by shortening poly(A) tail. PI3K, phosphoinositide-3-kinase; IL-2, interleukin 2.