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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

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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.

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Acknowledgments

This work was supported by Grants from the National Key Technologies Research and Development Program of China during the 11th 5-year Plan Period (No. 2008ZX10002-006), the Program for Changjiang Scholars and Innovative Research of Teamin University (No. IRT0872), and the National Science Foundation of China (No. 81172804). We also thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript.

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Authors and Affiliations

  1. 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

    Zhixin Yang, Yu Lei, Chunbo Chen, Hong Ren & Tongdong Shi

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  1. Zhixin Yang
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  2. Yu Lei
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Correspondence to Tongdong Shi.

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Yang, Z., Lei, Y., Chen, C. et al. 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. Arch Virol 160, 2535–2545 (2015). https://doi.org/10.1007/s00705-015-2539-3

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