細胞外リン脂質代謝がT細胞応答と炎症を制御する

2026-06-03 東京大学

Th17 細胞の分化を制御する細胞外脂質代謝

＜関連情報＞

• https://www.u-tokyo.ac.jp/content/400289062.pdf
• https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00469-9

PLA2G12Aを介した細胞外小胞脂質シグナル伝達は、炎症性疾患における病原性T細胞応答を増幅する PLA2G12A-driven extracellular vesicle-lipid signaling amplifies pathogenic T cell responses in inflammatory diseases

Chika Mochizuki-Ono ∙ Yoshitaka Taketomi ∙ Atsushi Irie ∙ … ∙ Yusuke Endo ∙ Junken Aoki ∙ Makoto Murakami
Cell Reports  Published:June 2, 2026
DOI:https://doi.org/10.1016/j.celrep.2026.117391

Highlights

• Genetic deletion or antibody neutralization of PLA2G12A prevents psoriasis and arthritis
• PLA2G12A hydrolyzes Th17-derived EVs to generate bioactive lysophospholipids
• Promotion of pathogenic Th17 differentiation by PLA2G12A depends on the LPA₂ receptor
• Defective Th17 differentiation by PLA2G12A loss is rescued by PLA2G12A-modified EVs

Summary

Extracellular vesicles (EVs) contribute to intercellular communication, yet how EV-driven lipid signaling is regulated in immune responses remains incompletely understood. Here, we show that genetic deficiency or antibody-mediated neutralization of PLA2G12A, a secreted phospholipase A₂ (sPLA₂) transiently upregulated in activated CD4⁺ T cells, prevents pathogenic Th17 differentiation and associated diseases including psoriasis and arthritis. PLA2G12A acts on T cell-derived EVs to produce lysophospholipids including the RORγt activator 1-oleoyl-lysophosphatidylethanolamine. Furthermore, these lysophospholipids are converted by autotaxin to lysophosphatidic acid, which amplifies Th17 differentiation via the LPA₂ receptor. Moreover, PLA2G12A promotes the secretion and uptake of EVs by Th17 cells and alters their cargo contents. Defective Th17 differentiation by PLA2G12A deficiency is restored by supplementation with PLA2G12A-modified EVs. These results provide a rationale for the sPLA₂-EV-lysophospholipid axis as a general mode of sPLA₂ action and suggest that targeting PLA2G12A may be useful for the treatment of Th17-related or possibly other inflammatory diseases.