TIPE2 protein restrains invariant NKT activation and protects against immune-mediated hepatitis in mice

Background and Aims: Concanavalin A (ConA) administration induces a rapid and severe liver injury in mice, and invariant natural killer T (iNKT) cells are recognized to be the key effector cells in this process. However, the underlying regulatory mechanisms are not well defined. Approach and Results: We found that iNKT cells constitutively expressed TIPE2 (Tumor necrosis factor-α-induced protein 8-like 2, or TNFAIPL2). Genetic TIPE2 ablation strongly sensitized mice to ConA-induced hepatitis, accompanied with hyperactivation of iNKT cells. Moreover, Tipe2 -/- mice were also more susceptible to α-galactosylceramide (αGalCer)-induced liver injury, with elevated serum ALT level and enhanced proinflammatory cytokine production. CD1d signaling blockade or iNKT cell elimination through antibodies reduced the effect of TIPE2 deficiency on liver injury. Mechanistic studies revealed that TIPE2 in iNKT cells functioned as a negative regulator, limiting iNKT cell activity and cytokine production through PIP3- AKT/mTOR pathway. TIPE2-mediated protection from liver injury was further validated by the administration of adeno-associated viruses expressing TIPE2, which effectively ameliorated ConA-induced hepatic injury. However, TIPE2 was dispensable in two other liver injury models, including D-GalN/LPS and APAP-induced hepatitis. Conclusion: Our findings reveal a new role of TIPE2 in the attenuation of iNKT cell-mediated hepatic injury. We propose that TIPE2 serves as an important regulator of immune homeostasis in the liver, and might be exploited for the therapeutic treatment of autoimmune liver diseases.