2. Academic Validation
  3. TCR-NF-κB signaling activates the SENP1-NR4A1 axis to fine-tune effector activation of CD8+ T cells

TCR-NF-κB signaling activates the SENP1-NR4A1 axis to fine-tune effector activation of CD8+ T cells

  • Cell Rep. 2026 Mar 24;45(3):117102. doi: 10.1016/j.celrep.2026.117102.
Cen Jiang 1,  Yuquan Yang 1,  Jing Tian 1,  Zi Liang 1,  Qiuju Fan 1,  Qi Wang 2,  Lei Shen 3,  Shengdian Wang 4,  Jianli He 5,  Jinke Cheng 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 5 Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 6 Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Hainan Medical University, Hainan Academy of Medical Sciences, Haikou, Hainan, China. Electronic address: [email protected].
PMID: 41831233 DOI: 10.1016/j.celrep.2026.117102
Abstract

T cell receptor (TCR) signaling plays a crucial role in T cell activation by creating a negative controlling mechanism to limit the strength of immune activation; however, the underlying mechanisms remain to be fully elucidated. Here, we identify the small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) as a target of the TCR-NF-κB signaling pathway that negatively regulates TCR-induced CD8+ T cell activation. SENP1 deficiency promotes the early occurrence of TCR-induced CD8+ T cell proliferation and effector gene expression. Mechanistically, the nuclear receptor NR4A1 is identified as a deSUMOylation target of SENP1 during this process. SENP1-mediated deSUMOylation of NR4A1 enhances its suppressive effect on the expression of TCR-induced effector genes in CD8+ T cells. Deficiency in the SENP1-NR4A1 axis markedly enhances the CD8+ T cell response against L. monocytogenes Infection. Collectively, these findings identify SENP1 as a crucial regulator that integrates TCR-NF-κB signaling with NR4A1 activity to fine-tune the CD8+ T cell-mediated immune response.

Keywords

CD8(+) T cell; CP: immunology; NR4A1; SENP1; SUMOylation; T cell receptor.

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