JAK/STAT signaling is involved in IL-35-induced inhibition of hepatitis B virus antigen-specific cytotoxic T cell exhaustion in chronic hepatitis B

• Published in: Life sciences (1973) Vol. 252; pp. 117663 - 7
• Main Authors: Dong, Yuejiao, Li, Xuefen, Yu, Yanying, Lv, Feifei, Chen, Yu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2020; Elsevier BV
• Subjects: Antigens; Apoptosis; automation; blood serum; CD223 antigen; Cell activation; Chronic hepatitis B; Confocal microscopy; Cytokines; Cytotoxicity; Deoxyribonucleic acid; DNA; Exhaustion; Flow cytometry; genes; Hepatitis; Hepatitis B; Hepatitis B virus; Hepatitis B virus-specific cytotoxic T lymphocyte; Immunotherapy; Interferon; Interferon gamma; Interleukin 12; Interleukin-35; JAK/STAT; Janus kinase; Kinases; lymphocyte proliferation; Lymphocytes; Lymphocytes T; Necrosis; non-specific protein-tyrosine kinase; PD-1 protein; protein content; Protein-tyrosine kinase; Proteins; quantitative polymerase chain reaction; receptors; reverse transcriptase polymerase chain reaction; signal transduction; Stat1 protein; Stat4 protein; T-lymphocytes; transactivators; Transcription; Tyk2 protein; Tyrosine; Viruses; Hepatitis B virus-specific cytotoxic T lymphocyte; JAK/STAT; Chronic hepatitis B; Interleukin-35; Interferon gamma
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2020.117663

Interleukin-35 (IL-35) is a new member of the interleukin-12 family and is composed of the P35 and EB virus-inducible gene 3 subunits. The aims of this study were to examine the roles of IL-35 in the exhaustion of HBV-specific CTLs, as little as known on the subject. The relative levels of serum HBV markers were detected using automated biochemical techniques. The HBV DNA copies were measured by RT-qPCR. The expression of inhibitory receptors and the cell cytokines on the surface of CTLs were determined by flow cytometry. The pSTAT1-pSTAT4 protein levels expression was determined by flow cytometry, confocal microscopy and Western blot. Our results showed that IL-35 can activate the Janus kinase 1 (JAK1)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription 1 (STAT1)/STAT4 pathway in CTLs in vitro. Interferon-γ and tumor necrosis alpha-α expression increased in CTLs in the presence of a JAK/STAT-pathway blocker. In addition, we evaluated the expression of the exhaustion-associated molecules programmed death-1, cytotoxic T lymphocyte-associated protein-4, and lymphocyte activation gene-3 in CTLs after adding the JAK-STAT inhibitor The results showed that the expression of exhaustion-associated molecules on the CTL surface decreased after blocking the JAK-STAT pathway. IL-35 inhibited the function of HBV-specific CTLs through the JAK1/TYK2/STAT1/STAT4 pathway, and the function of CTLs was recovered after blocking the JAK/STAT pathway. These data provide a new experimental basis for immunotherapy for chronic hepatitis B. •IL-35 activated the JAK1/TYK2/STAT1/STAT4 pathway in CTLs in vitro.•IFN-γ and TNF-α increased in CTLs in the presence of a JAK/STAT-pathway blocker.•Exhaustion-associated molecules decreased in CTLs after JAK/STAT inhibition.•IL-35 inhibited the function of HBV-specific CTLs through the JAK/STAT pathway.•These data provide a rational basis for immunotherapy for chronic hepatitis B.