mTOR aggravated CD4+ T cell pyroptosis by regulating the PPARγ–Nrf2 pathway in sepsis

Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. CD4⁺T cell reduction is crucial to sepsis-induced immunosuppression. Pyroptosis, a programmed necrosis, is concerned with lymphocytopenia. Peroxisome proliferator-activated receptor gamma (PPARγ) regulated by upstream mTOR, exerts anti-pyroptosis effects. To investigate the potential effects of mTOR-PPARγ on sepsis-induced CD4⁺T cell depletion and the underlying mechanisms, we observed mTOR activation and pyroptosis with PPARγ-Nrf suppression through cecal ligation and puncture (CLP) sepsis mouse model. Further mechanism research used genetically modified mice with T cell-specific knockout mTOR or Tuberous Sclerosis Complex1 (TSC1). It revealed that mTOR mediated CD4 + T cell pyroptosis in septic mice by negatively regulating the PPARγ-Nrf2 signaling pathway. Taken together, mTOR-PPARγ-Nrf2 signaling mediated the CD4⁺ T cell pyroptosis in sepsis, contributing to CD4⁺T cell depletion and immunosuppression.