Peroxisome Proliferator-activated Receptor γ-induced T Cell Apoptosis Reduces Survival during Polymicrobial Sepsis

Rationale: Despite intensive research, sepsis displays the most prevalent cause of death on intensive care units. The hallmark of sepsis is an overshooting T-cell death that reduces host defense mechanisms and that is associated with poor patient survival. Previous in vitro studies revealed that the expression of the transcription factor peroxisome proliferator-activated receptor (PPAR) gamma was increased in isolated T cells of patients with sepsis. Objectives: We determined the importance of targeting PPAR gamma for sepsis treatment and underlying molecular mechanisms for T-cell apoptosis in vivo. Methods: To mimic human systemic inflammation and septic conditions, we used a nonlethal endotoxemia and a lethal cecum ligation and puncture polymicrobial sepsis model. Measurements and Main Results: PPAR gamma inhibition in T cells with either the PPAR gamma antagonist GW9662 or a newly generated T cell-specific PPAR gamma knockout (Tc-PPAR gamma(-/-)) mice provided a survival advantage during polymicrobial sepsis in mice, which correlated with abrogated T-cell depletion in both in vivo models. Pathway analysis revealed increased antiapoptotic IL-2 and Bcl-2 expression, and activated prosurvival PI3K/Akt signaling under PPAR gamma-deficient conditions. In line, neutralizing IL-2 in Tc-PPAR gamma(-/-) mice resulted in T-cell apoptosis and increased mortality. Conclusions: Our results provide evidence fora pivotal involvement of PPAR gamma in T-cell depletion by activating two important apoptosis pathways, and subsequently provoking the breakdown of defense mechanisms during systemic inflammation and sepsis.