title: γδT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance.
abstract: 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.
authors.affiliation: Department of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; and.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China;
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; and.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Immunology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China; and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors; D039481:CD11b Antigen / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D006509:Hepatitis B / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D007108:Immune Tolerance; D020381:Interleukin-17 / Q000235:genetics; D008099:Liver / Q000276:immunology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; C544448:Arg1 protein, mouse; D001119:Arginase