Epsilon Toxin from Clostridium perfringens Induces the Generation of Extracellular Vesicles in T-Lymphocytes.

Epsilon toxin (ETX) is a pore-forming toxin (PFT) capable of crossing the blood–brain barrier and binding to myelin structures. In vitro assays have demonstrated that ETX impairs oligodendrocytes and induces demyelination. Notably, ETX has been implicated in the pathogenesis of multiple sclerosis (MS), with ETX-specific antibodies detected in sera from MS patients.

Myelin and lymphocyte protein (MAL) is widely recognized as the receptor for ETX. Its presence is essential for ETX-induced pore formation in the plasma membrane of host cells, ultimately leading to cell death. Recent findings have shown that ETX also binds to and kills primary human lymphocytes, which express elevated levels of MAL. This suggests that ETX may influence immune responses associated with MS, although its precise mechanism of action remains unclear.

To counteract the damage caused by PFTs, some host cells release extracellular vesicles (EVs) to reduce pore insertion into the plasma membrane. ETX has been shown to induce EV production in HeLa cells overexpressing MAL-GFP. Similar effects have been observed in MOLT4 cells, a T-lymphocyte line that endogenously expresses MAL protein. Our observations confirm that ETX also stimulates EV formation in MOLT4 cells. Moreover, both MAL protein and ETX oligomers are present in these EVs, making them a valuable tool for investigating ETX’s mode of action and its interaction with its receptor. We speculate that these EVs may play a role in the induction of MS.