The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells

Background: Hepatitis D virus (HDV) Infection affects 15-20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV Infection.

Methods: Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used.

Results: Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8⁺ T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4⁺ and CD8⁺ T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus-specific T cells.

Conclusions: This investigation of virus-specific T-cell immunity in patients with HDV Infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12.

CD4 T cells; CD57; CD8 T cells; CTLA-4; IL-12; PD-1.