TY - JOUR
T1 - Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV
AU - Fang, Zhong
AU - Zhang, Yi
AU - Zhu, Zhaoqin
AU - Wang, Cong
AU - Hu, Yao
AU - Peng, Xiuhua
AU - Zhang, Dandan
AU - Zhao, Jun
AU - Shi, Bisheng
AU - Shen, Zhongliang
AU - Wu, Min
AU - Xu, Chunhua
AU - Chen, Jieliang
AU - Zhou, Xiaohui
AU - Xie, Youhua
AU - Yu, Hui
AU - Zhang, Xiaonan
AU - Li, Jianhua
AU - Hu, Yunwen
AU - Kozlowski, Maya
AU - Bertoletti, Antonio
AU - Yuan, Zhenghong
N1 - Publisher Copyright:
© 2022 Fang et al.
Funding Information:
This study was funded by the National Key R&D Program of China (No. 2021YFC2300602 to Z. Yuan), the National Natural Science Foundation of China (No. 91842309 to Z. Yuan), the Research Unit of Chronic Hepatitis B virus infection from China Academy of Medical Science (No. 2019RU037 to Z. Yuan), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01S131 to Z. Yuan), and the National Natural Science Foundation of China (No. 81471931 to Y. Hu).
Publisher Copyright:
© 2022 Fang et al.
PY - 2022/4/4
Y1 - 2022/4/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85125836592&partnerID=8YFLogxK
U2 - 10.1084/jem.20211838
DO - 10.1084/jem.20211838
M3 - Article
C2 - 35254403
AN - SCOPUS:85125836592
SN - 0022-1007
VL - 219
SP - 1
EP - 18
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
M1 - e20211838
ER -
