CD4(+) T cells license Kupffer cells to reverse CD8(+) T cell dysfunction induced by hepatocellular priming.

Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8(+) T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4(+) T cell receptor transgenic mice to show that CD4(+) effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8(+) T cell function and suppresses viral replication. CD4(+) T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4(+) T cells license Kupffer cells via CD40-CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4(+) T cell pool, while IL-27 is essential for CD8(+) T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8(+) T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.