Recently, the research team of Maike Hofmann and Robert Thimme from the University of Freiburg in Germany published an article titled "Attenuated effector T cells are linked to control of chronic HBV infection" in Nature Immunology, and found that in chronic Hepatitis B virus (HBV) infection, in addition to classic CD8+T cell exhaustion, effector CD8+T cell attenuation also occurs. HBV-specific CD8+T cell attenuation is manifested by cytotoxic characteristics and inhibition of effector differentiation programs. This process is regulated by antigen recognition and TGFβ signaling and is associated with viral control in chronic HBV infection.
The researchers first obtained HBV-specific CD8+ T cells from patients with chronic HBV infection, performed single-cell RNA-seq, analyzed their transcriptional heterogeneity, and found 5 different cell populations. In order to study the effect of target antigens on transcriptional heterogeneity, they clustered the single-cell transcriptomes of 1056 HBV core18-specific and 1284 HBV pol455-specific CD8+ T cells and found 4 populations. Among them, population 1 was enriched in cytotoxic gene expression and mainly composed of HBV pol455-specific CD8+ T cells, while the other 3 populations contained both HBV pol455-specific CD8+ T cells and HBV core18-specific CD8+ T cells. Further analysis found that most HBV pol455-specific CD8+ T cells expressed cytotoxic and effector cell differentiation markers. Therefore, they found a cytotoxic HBV pol455-specific CD8+ T cell subset in chronic HBV infection, which has effector cell characteristics but lacks T cell exhaustion markers.
Figure 1. Distinct subsets of HBV core18- and HBV pol455-specific CD8+ T cells. (Heim K, et al., 2024)
To further investigate the biological relevance of this class of cytotoxic CD8+ T cells in chronic HBV infection, they performed transcriptional analysis of HBV pol455-specific CD8+ T cells from two groups of patients with chronic HBV infection: patients with intrinsic control of the virus who do not require antiviral therapy, and patients with chronic hepatitis B (CHB) who require antiviral therapy. The analysis revealed the presence of three distinct cell populations, the major of which was a cytotoxic cell population that was strongly associated with intrinsic control of the virus.
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During chronic HBV infection, cytotoxic CD8+T cell responses are weakened. They then performed single-cell transcriptome analysis and found that these attenuated HBV pol455-specific CD8+T cells had a unique transcriptional program compared with classical effector T cells, and TGFBR3 expression was specifically upregulated, suggesting an upregulation of TGFβ response. Inhibition of the TGFβ signaling pathway led to a reduction in IFNγ and TNF production by HBV pol455-specific CD8+T cells. Therefore, TGFβ signaling may be a core regulator of HBV pol455-specific CD8+T cell attenuation.
Overall, this study revealed the existence of a class of attenuated cytotoxic HBV-specific CD8+T cell populations during chronic HBV infection. This type of cell is associated with intrinsic control of the virus, providing a relevant theoretical basis for the treatment of hepatitis B.
Reference
Heim K, et al. Attenuated effector T cells are linked to control of chronic HBV infection. Nature Immunology, 2024: 1-13.