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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Imene Hamaidi,
  • Pingyan Cheng,
  • Soo Young Jun,
  • Alak Manna,
  • Min-Hsuan Wang,
  • Anh Nguyen,
  • Ismail Can,
  • Min G. Zhang,
  • Odesha O. Taylor,
  • Luis Uriel Lopez Bailon,
  • Bin Fang,
  • Bradford Perez,
  • Ben C. Creelan,
  • Andriy Marusyk,
  • Dongjun Shin,
  • Tae Hyun Hwang,
  • Anders E. Berglund,
  • Virginia S. Shapiro,
  • Haitao M. Ji,
  • José R. Conejo-Garcia,
  • Sungjune Kim

摘要

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.