Lipid mediator palmitoylethanolamide (PEA) inhibits pathogenic T cell differentiation in vitro and in vivo

Lipid mediator, palmitoylethanolamide (PEA) has recently attracted attention as a potential therapeutic option for various inflammatory autoimmune diseases. It has been reported that PEA exerts an inhibitory effect on inflammation triggered by PRRs, particularly Toll-like receptors expressed on myeloid antigen-presenting cells. However, the precise role of PEA in T cell development and function has not yet been elucidated. Here, we found that PEA suppressed the differentiation of Type 1 T helper (Th1) cells and Th17 cells, which are known to cause autoimmune diseases, as well as Th2 cells, which are associated with allergic diseases. This suppression occurs by inhibiting the expression of the master transcription factors crucial for their differentiation in vitro. Notably, PEA had no impact on the process of differentiating regulatory T cells, which play a crucial role in preventing the onset of autoimmune diseases. To further confirm the effect of PEA in vivo, we administered PEA to a Toxoplasma gondii infection model and an ovalbumin-induced allergic rhinitis model. Mice infected with T. gondii, in which Th1 responses are important for pathogen eradication, exhibited enhanced susceptibility. Mice with allergic rhinitis, where Th2 responses contribute to an exacerbation of symptoms, showed alleviated symptoms. Collectively, these findings suggest that PEA has potential applications as a new therapeutic agent for inflammatory autoimmune and allergic diseases based on excessive T cell activity.