Heterogeneity of HBV-specific CD8+

Heterogeneity of HBV-specific CD8+ T cells is also existent on the level of the targeted antigens. Indeed, immunological characterization of transgenic mice has already shown a hierarchy of dominant and subdominant HBV antigens with various frequencies and antiviral activity (48–50). Recently, studies in chronically HBV-infected patients also observed different properties of HBV-specific CD8+ T cells targeting different HLA-A*02:01 restricted epitopes located in the core (core18−27: FLPSDFFPSV), envelope (env183−191: FLLTRILTI), and polymerase (pol455−463: GLSRYVARL) proteins (Table 1). First, the frequencies of HBV-specific CD8+ T cells targeting the different epitopes varied significantly. Core18-specific CD8+ T cells were present in a higher frequency compared to pol455-specific CD8+ T cells, whereas env183-specific CD8+ T cells were rarely detectable in patients with chronic HBV infection (47, 51). The low frequency of env183-specific CD8+ T-cell responses was generally related to the high levels of HBs antigen and is thus most likely caused by deletion as a consequence of hyperactivation. Second, differences within the CD127/PD1-based subset distribution were observed between core18- and pol455-specific CD8+ T cells in chronically HBV-infected patients. Precisely, pol455-specific CD8+ T cells showed a diminished proportion of the memory-like CD127+PD1+ subset compared to core18-specific CD8+ T cells (47). This finding together with the distinct expression of killer cell lectin like receptor G1 (KLRG1), Eomes and CD38 on pol455-specific CD8+ T cells reflected a higher degree of terminal T-cell exhaustion compared with core18-specific CD8+ T cells (47, 51). The different exhaustion profile of both HBV-specific CD8+ T-cell subpopulations was further underpinned by the functional analyses revealing decreased expansion capacity of pol455-specific CD8+ T cells which was linked to a dysregulated TCF1/BCL2 expression (47). Thus, these findings give a first hint that T-cell failure of HBV-specific CD8+ T-cell populations may occur due to different molecular mechanisms. Additionally, in both studies (47, 51), phenotypic and functional differences of HBV-specific CD8+ T cells targeting core vs. polymerase epitopes were also evident in the context of non-HLA-A*02 alleles (HLA-A*01:01: core30−38: LLDTASALY; HLA-A*11:01: core88−96: YVNVNMGLK; core141−150: STLPETVVRR; HLA-A24:02: core117−125: EYLVSFGVW, pol756−764: KYTSFPWLL; HLA-B*08:01: core123−130: GLKILQLL; HLA-B*35:01: core19−27: LPSDFFPSV, pol173−181: SPYSWEQEL; HLA-B51:01: core19−27: LPSDFFPSV; HLA-B*40:01: pol40−48: AEDLNLGNL) indicating an antigen-related phenomena. In line with this observation, another recent study also highlighted different exhaustion profiles of HBV-specific CD8+ T cells targeting different HLA-A*11:01 restricted epitopes within the core and polymerase antigens (core169−179: STLPETAVVRR and pol387−396: LVVDFSQFSR) (52). Furthermore, Cheng et al. showed that HBV-specific CD8+ T-cell heterogeneity is also associated with the status of HBV infection (52). Still, a more comprehensive study is required to precisely dissect the impact of epitope, HLA-restriction, antigen, and disease status on HBV-specific CD8+ T-cell heterogeneity. Another open point that needs to be addressed in future studies is the HBV-specific CD8+ T-cell heterogeneity within the liver since current studies have focused on circulating lymphocytes within the blood and thus the effect of a possible compartmentalization has not been taken into account. This knowledge might be of particular importance for immunotherapeutic approaches since different strategies have potentially to be applied to boost the heterogeneous HBV-specific CD8+ T-cell populations.