Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing 400038, China.
J Hepatol. 2020 Jan;72(1):45-56. doi: 10.1016/j.jhep.2019.08.024. Epub 2019 Sep 6.
BACKGROUND & AIMS: The role of hepatitis B virus (HBV)-specific CD4 T cells in patients with chronic HBV infection is not clear. Thus, we aimed to elucidate this in patients with chronic infection, and those with hepatitis B flares.
Through intracellular IFN-γ and TNF-α staining, HBV-specific CD4 T cells were analyzed in 68 patients with chronic HBV infection and alanine aminotransferase (ALT) <2x the upper limit of normal (ULN), and 28 patients with a hepatitis B flare. HBV-specific HLA-DRB10803/HLA-DRB11202-restricted CD4 T cell epitopes were identified.
TNF-α producing cells were the dominant population in patients' HBV-specific CD4 T cells. In patients with ALT <2xULN, both the frequency and the dominance of HBV-specific IFN-γ producing CD4 T cells increased sequentially in patients with elevated levels of viral clearance: HBV e antigen (HBeAg) positive, HBeAg negative, and HBV surface antigen (HBsAg) negative. In patients with a hepatitis B flare, the frequency of HBV core-specific TNF-α producing CD4 T cells was positively correlated with patients' ALT and total bilirubin levels, and the frequency of those cells changed in parallel with the severity of liver damage. Patients with HBeAg/HBsAg loss after flare showed higher frequency and dominance of HBV-specific IFN-γ producing CD4 T cells, compared to patients without HBeAg/HBsAg loss. Both the frequency and the dominance of HBV S-specific IFN-γ producing CD4 T cells were positively correlated with the decrease of HBsAg during flare. A differentiation process from TNF-α producing cells to IFN-γ producing cells in HBV-specific CD4 T cells was observed during flare. Eight and 9 HBV-derived peptides/pairs were identified as HLA-DRB10803 restricted epitopes and HLA-DRB11202 restricted epitopes, respectively.
HBV-specific TNF-α producing CD4 T cells are associated with liver damage, while HBV-specific IFN-γ producing CD4 T cells are associated with viral clearance in patients with chronic HBV infection.
TNF-α producing cells are the dominant population of hepatitis B virus (HBV)-specific CD4 T cells in patients with chronic HBV infection. This population of cells might contribute to the aggravation of liver damage in patients with a hepatitis B flare. HBV-specific IFN-γ producing CD4 T cells are associated with HBV viral clearance. Differentiation from HBV-specific TNF-α producing CD4 T cells into HBV-specific IFN-γ producing CD4 T cells might favor HBV viral clearance.
乙型肝炎病毒（HBV）特异性 CD4 T 细胞在慢性 HBV 感染患者中的作用尚不清楚。因此，我们旨在阐明慢性感染患者和乙型肝炎发作患者的 HBV 特异性 CD4 T 细胞情况。
通过细胞内 IFN-γ 和 TNF-α 染色，分析了 68 例 ALT<2x 正常值上限（ULN）的慢性 HBV 感染患者和 28 例乙型肝炎发作患者的 HBV 特异性 CD4 T 细胞。鉴定了 HBV 特异性 HLA-DRB10803/HLA-DRB11202 限制性 CD4 T 细胞表位。
TNF-α 产生细胞是患者 HBV 特异性 CD4 T 细胞中的主要群体。在 ALT<2xULN 的患者中，随着病毒清除水平的升高，HBV e 抗原（HBeAg）阳性、HBeAg 阴性和 HBV 表面抗原（HBsAg）阴性患者的 HBV 特异性 IFN-γ 产生 CD4 T 细胞的频率和优势依次增加。在乙型肝炎发作患者中，HBV 核心特异性 TNF-α 产生 CD4 T 细胞的频率与患者的 ALT 和总胆红素水平呈正相关，并且这些细胞的频率与肝损伤的严重程度平行变化。乙型肝炎发作后 HBeAg/ HBsAg 丢失的患者与无 HBeAg/ HBsAg 丢失的患者相比，HBV 特异性 IFN-γ 产生 CD4 T 细胞的频率和优势更高。HBV S 特异性 IFN-γ 产生 CD4 T 细胞的频率和优势与乙型肝炎发作期间 HBsAg 的下降呈正相关。在乙型肝炎发作期间，HBV 特异性 CD4 T 细胞中观察到从 TNF-α 产生细胞向 IFN-γ 产生细胞的分化过程。分别鉴定出 8 个和 9 个 HBV 衍生肽/对作为 HLA-DRB10803 限制性表位和 HLA-DRB11202 限制性表位。
HBV 特异性 TNF-α 产生 CD4 T 细胞与慢性 HBV 感染患者的肝损伤有关，而 HBV 特异性 IFN-γ 产生 CD4 T 细胞与 HBV 病毒清除有关。
在慢性 HBV 感染患者中，TNF-α 产生细胞是 HBV 特异性 CD4 T 细胞的主要群体。该细胞群可能导致乙型肝炎发作患者的肝损伤加重。HBV 特异性 IFN-γ 产生 CD4 T 细胞与 HBV 病毒清除有关。从 HBV 特异性 TNF-α 产生 CD4 T 细胞向 HBV 特异性 IFN-γ 产生 CD4 T 细胞的分化可能有利于 HBV 病毒的清除。
