A liver-tissue rheostat limits T cell receptor signaling and impairs function of virus-specific CD8 T cells in chronic viral hepatitis

While acute hepatitis B virus (HBV) infections are controlled by a robust, antiviral CD8 T cell response, CD8 T cells are scarce and dysfunctional in chronic HBV infections. Here we demonstrate that the underlying mechanisms responsible for the functional inhibition of CD8 T cells during persistent hepatic infections is driven by the microenvironment of the liver.

To analyze antigen-specific immunity, we utilized a preclinical model system based on hepatotropic, recombinant adenoviruses to transfer the HBV genome into hepatocytes, thereby inducing acute-resolving or persistent infections. Subsequently, we conducted analysis on these tissues by using confocal microscopy and by isolating antigen-specific CD8 T cells and subjecting them to analysis by flow cytometry and RNA sequencing. Using in vitro co-cultures, we could further investigate interactions between hepatic cells and CD8 T cells.

In persistent viral infections antigen-specific CD8 T cells establish a close contact with liver sinusoidal endothelial cells (LSEC). These CD8 T cells revealed elevated protein kinase A (PKA) phosphorylation, increased activity of cAMP responsive element modulator (CREM) and consequently impaired T cell receptor signaling causing loss of effector function. Pharmacological blockade of the adenylyl-cyclase-cAMP-PKA axis as well as knockdown of adenylyl cyclase in T cells rescued the dysfunctional CD8 T cells. Co-culture of CD8 T cells with LSECs in vitro phenocopied increased PKA phosphorylation and revealed molecule exchange from LSECs to CD8 T cells.

Thus, close contact with LSECs during persistent, hepatotropic infections curbs the function of antigen-specific effector CD8 T cells in a rheostat-like fashion via the adenylyl cyclase-cAMP-PKA axis.

Publication History

Article published online:
20 January 2025