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Updated: Jun 12, 2025
Purification and Expansion of Mouse Invariant Natural Killer T Cells for in vitro and in vivo Studies
Published on: February 15, 2021
TIPE2 protein restrains invariant NKT activation and protects against immune-mediated hepatitis in mice
Miaomiao Song1, Han Wang1, Xueqin Tian1,2,3
1Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China.
Background And Aims:
Concanavalin A (ConA) administration induces 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 by hyperactivation of iNKT cells. Moreover, Tipe2-/- mice were also more susceptible to α-galactosylceramide-induced liver injury, with elevated serum ALT levels 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 2 other liver injury models, including D-GalN/LPS and acetaminophen-induced hepatitis.
Conclusions:
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.
Insights
Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) restrains invariant natural killer T (iNKT) cell activity, protecting against Concanavalin A-induced liver injury. TIPE2 deficiency exacerbates hepatitis, highlighting its role in immune homeostasis.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Invariant natural killer T (iNKT) cells are key effectors in Concanavalin A (ConA)-induced liver injury.
- Regulatory mechanisms governing iNKT cell-mediated liver injury remain incompletely understood.
Purpose of the Study:
- To elucidate the role of TIPE2 (tumor necrosis factor-α-induced protein 8-like 2) in regulating iNKT cell-mediated liver injury.
- To investigate TIPE2's potential as a therapeutic target for autoimmune liver diseases.
Main Methods:
- Analysis of TIPE2 expression in iNKT cells.
- Assessment of ConA-induced liver injury in wild-type and TIPE2-deficient (Tipe2-/-) mice.
- Investigation of signaling pathways involved in TIPE2 function.
- Therapeutic intervention using adeno-associated viruses expressing TIPE2.
Main Results:
- iNKT cells constitutively express TIPE2.
- Tipe2-/- mice exhibited heightened susceptibility to ConA and α-galactosylceramide-induced liver injury, with hyperactivated iNKT cells.
- TIPE2 negatively regulates iNKT cell activity and cytokine production via the PIP3-AKT/mTOR pathway.
- Adeno-associated virus-mediated TIPE2 delivery ameliorated ConA-induced hepatitis.
- TIPE2 was not essential in D-GalN/LPS or acetaminophen-induced liver injury models.
Conclusions:
- TIPE2 acts as a crucial negative regulator of iNKT cell-mediated hepatic injury.
- TIPE2 plays a significant role in maintaining liver immune homeostasis.
- TIPE2 represents a potential therapeutic target for autoimmune liver diseases.
