JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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γδT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance.

Journal of Immunology 2014 August 16
The mechanisms of liver hepatitis B virus (HBV)-induced systemic immune tolerance are still elusive, and the role of γδT cells has not yet been described. We examined the function of γδT cells in HBV-carrier mice--immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that γδT 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 TCRδ(-/-) mice in terms of losing HBV persistence, and adoptive transfer of γδT cells restored HBV-persistent expression in TCRδ(-/-) 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 TCRδ(-/-) and IL-17(-/-) mice. MDSC numbers also recovered after adoptive transfer of γδT cells, particularly Vγ4(+) T cells. Furthermore, anti-Gr1-mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to γδT 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 TCRδ(-/-) mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRδ(-/-) mice not only exhibited increased anti-HBV CD8(+) T cells but also markedly reduced MDSCs. Overall, the current study reveals that γδT 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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