CD8⁺ T cell/IL-33/ILC2 axis exacerbates the liver injury in Con A-induced hepatitis in T cell-transferred Rag2-deficient mice

Background: Previous studies showed that CD4⁺ T cells play a critical role in Con A-induced hepatitis in wild-type mice. However, the role of CD8⁺ T cells in the setting of Con A-induced hepatitis is enigmatic. The aim of study is to investigate the function of CD8⁺ T cells in the context of Con-A-induced hepatitis.

Materials and subjects: Two different mouse models of Con A-induced hepatitis, T cell-transferred Rag2^-/- mice and wild-type C57BL/6 mice, were used in the present study. IL-33 gene knockout mice were used to confirm the role of alarmin in Con A-induced hepatitis.

Results: Opposing to the previous results obtained in wild-type mice, transferred CD4⁺ T cells alone into Rag2-knockout mice cannot cause hepatitis upon Con A challenge. In stark contrast, transferred CD8⁺ T cells play an important role in the pathogenesis of Con A-induced liver injury in T cell-transferred Rag2-deficient mice. Furthermore, we found that hepatocytes injured by perforin-based CD8⁺ T cell cytotoxicity release the alarmin IL-33. This cytokine promotes ST2⁺ ILC2 development and the secretion of cytokines IL-5 and IL-13 to mediate liver inflammation triggered by Con A challenge. In addition, these type 2 cytokines, including those originated from CD4⁺ T cells, result in eosinophils accumulation in liver to exacerbate the liver injury after Con A administration.

Conclusion: Our data for the first time revealed that CD8⁺ T cells play an indispensable role in the pathogenesis of Con A-induced liver injury in T cell-transferred Rag2-deficient mice. Therefore, the CD8⁺ T cell/IL-33/ILC2 axis is a potential therapeutic target for acute immune-mediated liver injury.