Journal
JOURNAL OF IMMUNOLOGY
Volume 195, Issue 10, Pages 4873-4883Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1501362
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Funding
- National Key Basic Research Program [2012CB519005]
- National Megaprojects for Infectious Diseases [2008ZX10203]
- German Research Foundation [SFB/Transregio TRR60]
- National Natural Science Foundation of China [81471931]
- Multidisciplinary Creative Talents Training Program of Fudan University
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Chronic hepatitis B virus (HBV) infection is characterized by T cell tolerance to virus. Although inhibition of T cell responses by myeloid-derived suppressor cells (MDSCs) has been observed in patients with chronic hepatitis B (CHB), the mechanism for expansion of MDSCs remains ambiguous. In this study, a significant increased frequency of monocytic MDSCs (mMDSCs) was shown positively correlated to level of HBsAg in the patients with CHB. We further found hepatitis B surface Ag (HBsAg) efficiently promoted differentiation of mMDSCs in vitro, and monocytes in PBMCs performed as the progenitors. This required the activation of ERK/IL-6/STAT3 signaling feedback. Importantly, the mMDSCs polarized by HBsAg in vitro acquired the ability to suppress T cell activation. Additionally, treatment of all-trans retinoic acid, an MDSC-targeted drug, restored the proliferation and IFN-gamma production by HBV-specific CD4(+) and CD8(+) T cells in PBMCs from patients with CHB and prevented increase of viral load in mouse model. In summary, HBsAg maintains HBV persistence and suppresses T cell responses by promoting differentiation of monocytes into mMDSCs. A therapy aimed at the abrogation of MDSCs may help to disrupt immune suppression in patients with CHB.
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