Imène Hamaidi, Pingyan Cheng, Soo Young Jun, Alak Manna, Min-Hsuan Wang, Anh Nguyen, İsmail Can, M Zhang, Odesha O Taylor, Luis Uriel Lopez Bailon, Bin Fang, Bradford Perez, Ben C. Creelan, Andriy Marusyk, Dongjun Shin, Tae Hyun Hwang, Anders Berglund, Virginia Smith Shapiro, Haitao Mark Ji, José R. Conejo-García, Sungjune Kim
T cell receptor (TCR) signaling is precisely tuned to prevent self-reactivity while allowing protective immunity. Here we found that acetylation modulated TCR signaling. The loss of SIRT2 deacetylase activity in T cells led to amplified calcium mobilization and phosphorylation of key proximal TCR molecules in naive T cells and reversed dampened TCR signaling in anergic T cells. During thymic selection, SIRT2 deficiency lowered the TCR signaling threshold and resulted in a broader TCR repertoire diversity. Mechanistically, we identified acetyl-lysine K228 on the linker region of LCK as a substrate specific for SIRT2 that governed LCK conformation and activity. SIRT2 inhibition in exhausted mouse and human tumor-infiltrating T cells restored TCR responsiveness and antitumor immunity. These findings highlighted SIRT2-modulated protein acetylation as a regulatory mechanism that set the TCR threshold in T cells.