Impaired PTEN Expression in T Cells Drives Resistance to Treg-Mediated Immune Regulation in Multiple Sclerosis

The regulation of T cell-mediated immune responses is essential for maintaining immune homeostasis and preventing autoimmune diseases. In multiple sclerosis (MS), impaired immunoregulatory control allows autoreactive T cells to persist, as effector T cells (Teff) display reduced susceptibility to regulatory T cells (Treg). This resistance to Treg-mediated tolerance is linked to altered IL-6 signaling and hyperactivation of protein kinase B (PKB/c-Akt). However, the mechanisms leading to increased PKB phosphorylation remain poorly understood. Here, we examined the expression of phosphatase and tensin homolog PTEN, a key phosphatase that negatively regulates PKB/c-Akt activation. We found that PTEN protein expression rapidly declines in activated Teff from MS patients. To clarify whether PTEN downregulation contributes to Treg resistance, we used PTEN-specific siRNA to modulate PTEN expression in Teff from healthy donors. PTEN knockdown resulted in accelerated IL-6 production, enhanced PKB phosphorylation, and reduced responsiveness to Treg-mediated suppression, similar to Treg resistance observed in MS. This study reports disrupted PTEN expression in activated Teff from MS patients. Our findings highlight that PTEN is critical for effective immune regulation of T cells, and suggest its dysregulation contributes to impaired immune tolerance in MS.