Immune Regulation by T Regulatory Cells in Hepatitis B Virus-Related Inflammation and Cancer

Hepatocellular carcinoma (HCC) is the leading cause of cancer death, and hepatitis B virus (HBV) infection is one of the commonest causes in Asian countries. India has the second largest pool after China for hepatitis B-infected subjects. HBV clearance is T cell dependent, and one of the reasons for T cells hyporesponsiveness is due to mass production of regulatory T cells (Tregs) through activation of Notch signalling, which suppress CD4/CD8 T cells. Tregs are important to maintain cellular homoeostasis; however, during viral infection increase of Tregs is inversely proportional to HBV DNA titres. Tregs exert their suppressive effect either via cell-to-cell contact or through release of interleukin (IL)-2, IL-10, TGF-β and IL-35. In Chronic hepatitis B virus CHBV infection, PD-1 pathway also gets activated and is involved in promoting tolerance. However, with Tregs induction, virus-specific T cell responses also get decreased. Circulatory and intratumoural Tregs promote development of HBV-specific HCC more by decreasing and impairing the effector functions of CD8 T cells. Antiviral therapies and PD-1 blockade strategy had shown the inhibition of Tregs and reduction in HBV DNA. However, inhibition of HBV-specific Tregs is major challenge for future therapies. New cytokine blockade therapies have emerged as potential therapeutic potentials.