Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 4, Pages 1645-1653Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1303432
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Funding
- Natural Science Foundation of China [31390433, 31230025]
- Ministry of Science and Technology of China (973 Basic Science Project) [2012CB519004, 2013CB530506]
- National Science and Technology Major Projects [2013ZX10002002-002]
- Chongqing Science and Technology Department [cstc2013jcyjC10002]
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The mechanisms of liver hepatitis B virus (HBV)-induced systemic immune tolerance are still elusive, and the role of gamma delta T cells has not yet been described. We examined the function of gamma delta T cells in HBV-carrier mice--immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that gamma delta T cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8(+) T cells. Of interest, IL-17(-/-) mice phenocopied TCR delta(-/-) mice in terms of losing HBV persistence, and adoptive transfer of gamma delta T cells restored HBV-persistent expression in TCR delta(-/-) mice. We further observed that hepatic CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCR delta(-/-) and IL-17(-/-) mice. MDSC numbers also recovered after adoptive transfer of gamma delta T cells, particularly V gamma 4(+) T cells. Furthermore, anti-Gr1-mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to gamma delta T cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8+ T cells and promoted HBV clearance. We also observed enhanced CD8(+) T cell number with a notable decline of MDSCs in TCR delta(-/-) mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCR delta(-/-) mice not only exhibited increased anti-HBV CD8(+) T cells but also markedly reduced MDSCs. Overall, the current study reveals that gamma delta T cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8(+) T cell exhaustion.
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