Lightning Talk & Poster Presentation CD1-MR1 Workshop 2025

Unraveling the Role of TAK1 in iNKT Cell Development, Proliferation, and Survival (#46)

Bobby Zuniga 1 2 3 , Jie Wang 1 2 4 , Kalpana Subedi 1 2 , Rachel Krevh 1 2 , Jugmohit Toor 1 2 , James Ge 1 2 , Steven L Brown 5 , Li Zhou 1 2 6 7 8 , Qing-Sheng Mi 1 2 6 7 8
  1. Department of Dermatology, Henry Ford Health , Detroit, Michigan, United States
  2. Immunology Research Program, Henry Ford Health , Detroit, Michigan, United States
  3. Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, Michigan, United States
  4. Department of Medicine, Michigan State University, East Lansing, Michigan, United States
  5. Department of Radiation Oncology, Henry Ford Health , Detroit, Michigan, United States
  6. Department of Medicine, Michigan State University, Detroit, Michigan, United States
  7. Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, United States
  8. Department of Internal Medicine, Henry Ford Health , Detroit, Michigan, United States

Invariant natural killer T (iNKT) cells are crucial to bridging innate and adaptive immunity, yet the precise mechanisms by which Tak1, a member of the MAP3k family, contributes to iNKT cell development remains poorly understood. To address this, we generated T cell specific conditional TAK1 knockout (TAK1fl/fl cKO) mice. Although TAK1 deletion did not significantly affect overall thymic cellularity, we observed a marked reduction in iNKT cells in both the thymus and peripheral immune organs of TAK1-deficient mice. Interestingly, analysis of iNKT cell developmental stages revealed comparable maturation through the early stages between TAK1-deficient mice and wild-type mice, as evidenced by similar expression of key maturation markers. However, TAK1 deletion led to significantly lower expression of PLZF, resulting in impaired differentiation of iNKT17 cells and reduced IL-17A production. Additionally, we observed a pronounced defect in iNKT cell proliferation, accompanied by increased apoptosis and pyroptosis. In vitro experiments further confirmed impaired iNKT cell proliferation and survival after treatment with a TAK1 inhibitor. These findings highlight the essential role of Tak1 in iNKT cell development, proliferation, and survival, suggesting its potential as a therapeutic target for diseases associated with iNKT cell dysfunction.