Research

Major Research Interest: T cell quiescence 

T cells are considered as the master guardians that protect our body through distinguishing self and non-self and thereby govern the immune system during a human’s entire lifespan.  T cells are fated to firmly maintain the quiescent state prior to activation; however, little is known about the biology and factors that underlie this phenomenon.  As immunity is lifetime-regulated by a strict balance between quiescence and activation, deciphering the mechanism of T cells quiescence can provide a cornerstone for developing innovative therapeutics.  

For decades, T cell studies have solely focused on 1) activation, 2) differentiation, and 3) effector function. The research efforts have revealed the cell-extrinsic cues such as Signal 1 (cognate antigen through TCR), Signal 2 (co-stimulatory signals), and Signal 3 (stimulatory cytokines)  that accounts for the initiation of T cell activation and differentiation. However, this cell-extrinsic mechanism is insufficient to illustrate how most T cells normally sustain quiescence while inhibiting spontaneous activation. 

• How are the quiescent T cells remained in the poised state and prepared for rapid transition to an activated state?  

• Which are intrinsic features essential for the maintenance of quiescence? 

• What does define their threshold for quiescence exit? How are they wired?  

• How are the quiescent T cells strictly preventing spontaneous activation? 

By utilizing genetically modified mice and state-of-the-art immunological and molecular biological techniques with multidisciplinary collaboration,  we primarily focus on these questions to find out fundamental mechanisms on the process of quiescence to activation transition in T cells.

Recently, we identified that BTG1/2-mediated intrinsic deadenylation is required for securing T cell quiescence (Science, 2020). This work describes the hitherto unknown mechanism by which quiescent T cells actively sustain the ground state through an intrinsic system prior to activation. 

mRNA destabilization by BTG1 and BTG2 secures T cell quiescence

BTG1 and 2 are mainly expressed in naive and memory T cells. We found out that BTG1/2 interact with PABP and the CNOT complex in order to promote mRNA deadenylation and degradation. In this way, BTG1/2 can direct the down-regualtion of mRNAs at global level to restrict mRNA abundance in quiescent T cells. In BTG1/2 conditional knockout mice, total RNA-seq of naive T cells showed a global increase in mRNA abundance in DKO T cells, which allows naive T cells easily to exit from the quiescent state. It infers that mRNA abundance in naive T cells have the proclivity to be up-regulated, but BTG1/2 actively degrade the bulk of cytoplasmic mRNA to maintain quiescent state. This mechanism is seemingly inefficient in terms of cost, but the availability of pre-synthesized mRNA provides a great benefit to quiescent T cells of a rapid response to activation signals.  Science (2020) Mar 13;367(6483):1255-1260.