Global 
Deutschland Liver and Bile
Nature. 2024;631(8022):867–75
A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection
Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes. Here the authors demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12–22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, the authors found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation.
Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.
DOI: 10.1038/s41586-024-07630-7
Prof. Dr. Dr. Bertram Bengsch
Section Head for Translational Systems Immunology in Hepatogastroenterology, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
T cells amp’d down: Identification of a novel mechanism of intrahepatic immune regulation
The mechanisms by which hepatitis B virus (HBV) infection evades immune control through the T-cell response in chronic HBV (cHBV) infection are as yet unclear. Until recently, it has been assumed that this immune evasion is mediated primarily via the induction of T cell exhaustion, where virus-specific CD8 T cells are driven into a state of relative dysfunction, rendering them unable to clear viral infection due to an imbalance of immunological overstimulation and inhibitory signals. Here, Bosch et al. identify a distinct liver-specific immunoregulatory mechanism in a murine model of Ad-HBV infection. A subset of CXCR6+ HBV-specific CD8 T cells was regulated via the cAMP-protein kinase A (PKA) pathway activating the transcription factor CREM and lacked significant antiviral effector function. Unlike T-cell exhaustion associated with high transcriptional activity of Tox and strong T-cell receptor stimulation, these cells exhibited elevated phosphatase activity, which inhibited proximal TCR signaling without prominent Tox activity. Further analyses indicated that this regulatory pathway could be triggered through close interactions between HBV-specific CD8 T cells and liver sinusoidal endothelial cells (LSECs). Known for their immunological gatekeeping role in the liver, LSECs can reside next to virus-infected hepatocytes. The data suggests that LSEC cells contribute to attenuating the virus-specific CD8 T-cell response via an intrahepatic mechanism that effectively muffles TCR signaling. This has important implications for our understanding and targeting of T-cell responses against hepatic antigens.
While this study indicates that LSECs can coregulate HBV-specific CD8 T cells due to their spatial proximity when engaging HBV-infected hepatocytes, several aspects warrant further investigation. First, the precise triggers for this mechanism are still unclear, such as whether it necessitates simultaneous T-cell recognition of viral antigens presented by infected hepatocytes or specific hepatocyte-LSEC crosstalk. Second, further research is needed to understand the mediators involved in T-cell suppression. Third, questions remain about the durability of this regulatory effect and whether these CREM-signature T cells could be reprogrammed; the expression of co-stimulatory receptors suggests a potential for reactivation via agents such as 4-1BB agonists (DOI: 10.1016/j.cell.2024.05.038). Finally, it is uncertain what proportion of T-cell dysfunction in cHBV patients this mechanism accounts for. Recent single-cell RNA-Seq analysis of HBV-specific CD8 T cells identified heterogeneity, including T cells with signs of classic T-cell exhaustion, T cells with evidence of TGF-beta dependent effector attenuation, as well as a share of cells marked by CREM signatures (DOI: 10.1038/s41590-024-01928-4). Bosch et al. observe peak CREM activity in active hepatitis, suggesting that its role might be linked to a higher degree of liver inflammation. Overall this suggests that multiple mechanisms contribute to T-cell dysfunction in cHBV infection.