title: Roles of the programmed cell death 1, T cell immunoglobulin mucin-3, and cluster of differentiation 288 pathways in the low reactivity of invariant natural killer T cells after chronic hepatitis B virus infection.
abstract: One of the main responses of invariant natural killer T (iNKT) cells to antigen stimulation is the rapid production of interleukin (IL)-4 and interferon (IFN)-γ cytokines. There is a decline in the function of iNKT cells in chronic hepatitis B (CHB) patients. In this study, we explored the impact of programmed cell death 1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3), and cluster of differentiation 28 (CD28) expression on iNKT cell functions in CHB patients. Flow cytometry was used to test iNKT frequencies and levels of PD-1, Tim-3, CD28, IL-4, and IFN-γ secreted by iNKT cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure IL-4 and IFN-γ secretion upon α-galactosylceramide (α-GalCer) activation ex vivo. We found that the levels of expression of PD-1 and Tim-3 from iNKT cells in CHB patients were significantly higher than in healthy donors (p < 0.05), but there was lower expression of CD28 (p < 0.05) and an impaired capability to produce IL-4 and IFN-γ (p < 0.05). In vitro α-GalCer stimulation upregulated the expression of PD-1(+) iNKT cells (p < 0.05), Tim-3(+) iNKT cells (p < 0.05), and CD28(+) iNKT cells (p < 0.05). In response to combination therapies consisting of α-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-Tim-3 mAbs and/or anti-CD80/anti-CD28 mAbs, IL-4(+) and IFN-γ(+) iNKT cells demonstrated different degrees of growth (p < 0.05). The functional decline of iNKT cells was closely related to the decrease in CD28 expression and the increases of Tim-3 and PD-1. In addition, clinical antiviral treatment with lamivudine could partially restore the immune function of iNKT cells in CHB patients.
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute of Viral Hepatitis, Chongqing Medical University the Second Affiliated Hospital, 74 Linjiang Road, Chongqing, 400010, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute of Viral Hepatitis, Chongqing Medical University the Second Affiliated Hospital, 74 Linjiang Road, Chongqing, 400010, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute of Viral Hepatitis, Chongqing Medical University the Second Affiliated Hospital, 74 Linjiang Road, Chongqing, 400010, China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute of Viral Hepatitis, Chongqing Medical University the Second Affiliated Hospital, 74 Linjiang Road, Chongqing, 400010, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.affiliation: Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute of Viral Hepatitis, Chongqing Medical University the Second Affiliated Hospital, 74 Linjiang Road, Chongqing, 400010, China. 1452381090@qq.com.
authors.forename: Tongdong
authors.initials: T
authors.lastname: Shi
mesh_terms: D000328:Adult; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D006515:Hepatitis B virus / Q000276:immunology / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508598:IL4 protein, human; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D015847:Interleukin-4; D007371:Interferon-gamma