SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling

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Abstract
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.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (R37CA248298)
  • U.S. Department of War (CDMRP W81XWH-22-1-0860)
  • Mayo Clinic | Center for Clinical and Translational Science, Mayo Clinic (TR002379)

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