TIPE2 protein negatively regulates HBV-specific CD8+ T lymphocyte functions in humans

• TIPE2 in CD8+ T cells was decreased by HBV infection. CD8+ T cells with low TIPE2 protein levels were overactive and induced more severe hepatitis.

Cytotoxic T cell-mediated killing of virus-infected hepatocytes is an important pathogenic process of hepatitis B. However, its underlying molecular mechanisms are not fully understood. TNFAIP8L2 (TIPE2) is a newly described anti-inflammatory protein that is essential for maintaining immune homeostasis. In this study, we found that the protein levels of TIPE2 in PBMCs of hepatitis B patients were significantly reduced and negatively correlated with the sera values of aminotransferases. Importantly, TIPE2 protein was downregulated preferentially in cytotoxic CD8+ T cells, not CD4+ helper T cells. The CD8+ T cells with low TIPE2 expression were more activated and produced higher levels of perforin, granzyme B, and IFN-γ. As a result, their cytolytic activity was markedly enhanced. Interestingly, HBc18–27 peptide stimulation could reduce TIPE2 expression in PBMCs. These results indicate that TIPE2 plays an important role in regulating HBV-specific CD8+ T cell functions in patients with hepatitis B.