Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV
Zhong Fang, Yi Zhang, Zhaoqin Zhu, Cong Wang, Yao Hu, Xiuhua Peng, Dandan Zhang, Zhao Jun, Bisheng Shi, Zhongliang Shen, Min Wu, Chunhua Xu, Jieliang Chen, Xiaohui Zhou, Youhua Xie, Hui Yu, Xiaonan Zhang, Jianhua Li, Yunwen Hu, Maya Kozlowski, Antonio Bertoletti, Zhenghong Yuan
Abstract
Hepatitis B virus exposure in children usually develops into chronic hepatitis B (CHB). Although hepatitis B surface antigen (HBsAg)-specific CD8+ T cells contribute to resolve HBV infection, they are preferentially undetected in CHB patients. Moreover, the mechanism for this rarely detected HBsAg-specific CD8+ T cells remains unexplored. We herein found that the frequency of HBsAg-specific CD8+ T cells was inversely correlated with expansion of monocytic myeloid-derived suppressor cells (mMDSCs) in young rather than in adult CHB patients, and CCR9 was upregulated by HBsAg on mMDSCs via activation of ERK1/2 and IL-6. Sequentially, the interaction between CCL25 and CCR9 mediated thymic homing of mMDSCs, which caused the cross-presentation, transferring of peripheral HBsAg into the thymic medulla, and then promoted death of HBsAg-specific CD8+ thymocytes. In mice, adoptive transfer of mMDSCs selectively obliterated HBsAg-specific CD8+ T cells and facilitated persistence of HBV in a CCR9-dependent manner. Taken together, our results uncovered a novel mechanism for establishing specific CD8+ tolerance to HBsAg in chronic HBV infection.