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

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.