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

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.

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Publication Details

Journal
Nature Immunology
Published
2026-01-29
DOI
https://doi.org/10.1038/s41590-025-02377-3
Citations
2
Primary Topic
Sirtuins and Resveratrol in Medicine
Type
article
Field-Weighted Citation Impact
54.36
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article

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

Alak Manna, Andriy Marusyk, İsmail Can, M Zhang et al.
2 citations
Nature Immunology
Sirtuins and Resveratrol in Medicine
54.36
article

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

Alak Manna, Andriy Marusyk, İsmail Can, M Zhang, Lucía Bailón, Tae Hyun Hwang, Anders Berglund, Virginia Smith Shapiro, Sungjune Kim, Soo Young Jun, Jose Ramon Conejo-Garcia, Bin Fang, Imène Hamaidi, Haitao Mark Ji, Odesha O Taylor, Anh Nguyen, Ben C. Creelan, Min-Hsuan Wang, Pingyan Cheng, Dongjun Shin
article en
2 citations

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.

Nature ImmunologyVol. 27(2)
Mayo Clinic (US), Duke University (US), Vanderbilt University (US), Jacksonville College (US), Trinity College of Florida (US), WinnMed (US), Taipei Veterans General Hospital (TW), TomTom (Netherlands) (NL), Moffitt Cancer Center (US), Florida Cancer Specialists & Research Institute (US), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), University of Tampa (US)
Openalex Percentile: Top 0%
Sirtuins and Resveratrol in Medicine
54.36
DOIOpen Access PDFOpenAlex
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