PMID- 34297096
OWN - NLM
STAT- MEDLINE
DCOM- 20220203
LR  - 20220203
IS  - 1460-2377 (Electronic)
IS  - 0953-8178 (Linking)
VI  - 33
IP  - 9
DP  - 2021 Aug 23
TI  - Helicobacter urease suppresses cytotoxic CD8+ T-cell responses through activating 
      Myh9-dependent induction of PD-L1.
PG  - 491-504
LID - 10.1093/intimm/dxab044 [doi]
AB  - As a key virulence factor for persistent colonization, urease B subunit (UreB) is 
      considered to be an ideal vaccine antigen against Helicobacter pylori infection. 
      However, the role and molecular mechanisms of UreB involved in immune 
      microenvironment dysregulation still remain largely unknown. In the present 
      study, we evaluated the effects of UreB on macrophage activation and found that 
      UreB induced PD-L1 accumulation on bone marrow-derived macrophages (BMDMs). 
      Co-culture assays further revealed that UreB-induced PD-L1 expression on BMDMs 
      significantly decreased the proliferation and secretion of cytolytic molecules 
      (granzyme B and perforin) of splenic CD8+ T cells isolated from inactivated H. 
      pylori-immunized mice. More importantly, using liquid chromatography-tandem mass 
      spectrometry (LC-MS/MS) and co-immunoprecipitation techniques, it has been 
      confirmed that myosin heavy chain 9 (Myh9) is a direct membrane receptor for UreB 
      and is required for PD-L1 up-regulation on BMDMs. Molecular studies further 
      demonstrated that the interaction between UreB and Myh9 decreased GCN2 
      autophosphorylation and enhanced the intracellular pool of amino acids, leading 
      to the up-regulation of S6K phosphorylation, a commonly used marker for 
      monitoring activation of mTORC1 signaling activity. Furthermore, blocking mTORC1 
      activation with its inhibitor Temsirolimus reversed the UreB-induced PD-L1 
      up-regulation and the subsequent inhibitory effects of BMDMs on activation of 
      cytotoxic CD8+ T-cell responses. Overall, our data unveil a novel 
      immunosuppressive mechanism of UreB during H. pylori infection, which may provide 
      valuable clues for the optimization of H. pylori vaccine.
CI  - (c) The Japanese Society for Immunology. 2021. All rights reserved. For 
      permissions, please e-mail: journals.permissions@oup.com.
FAU - Wu, Jian
AU  - Wu J
AD  - Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and 
      Children, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan 430016, P.R. China.
FAU - Zhu, Xiaowen
AU  - Zhu X
AD  - Department of Gastroenterology, Affiliated Taihe Hospital of Hubei University of 
      Medicine, Shiyan 442099, P.R. China.
FAU - Guo, Xia
AU  - Guo X
AD  - Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and 
      Children, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan 430016, P.R. China.
FAU - Yang, Ze
AU  - Yang Z
AD  - Blood Transfusion Department, The Second Affiliated Hospital of Shandong First 
      Medical University, Taian 271000, P.R. China.
FAU - Cai, Qinzhen
AU  - Cai Q
AD  - Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and 
      Children, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan 430016, P.R. China.
FAU - Gu, Dongmei
AU  - Gu D
AD  - Department of Clinical Laboratory, Tianjin Medical University General Hospital, 
      Tianjin 300052, P.R. China.
FAU - Luo, Wei
AU  - Luo W
AD  - Department of Clinical Laboratory, Tianjin Medical University General Hospital, 
      Tianjin 300052, P.R. China.
FAU - Yuan, Chunhui
AU  - Yuan C
AD  - Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and 
      Children, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan 430016, P.R. China.
FAU - Xiang, Yun
AU  - Xiang Y
AD  - Department of Laboratory Medicine, Wuhan Medical and Health Center for Women and 
      Children, Tongji Medical College, Huazhong University of Science and Technology, 
      Wuhan 430016, P.R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Int Immunol
JT  - International immunology
JID - 8916182
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Bacterial Proteins)
RN  - 0 (CD274 protein, human)
RN  - 0 (MYH9 protein, human)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 3.5.1.5 (Urease)
RN  - EC 3.6.4.1 (Myosin Heavy Chains)
SB  - IM
MH  - Animals
MH  - B7-H1 Antigen/*immunology
MH  - Bacterial Proteins/*immunology
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Helicobacter Infections/*immunology
MH  - Helicobacter pylori/*immunology
MH  - Humans
MH  - Interferon-gamma/immunology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Myosin Heavy Chains/*immunology
MH  - RAW 264.7 Cells
MH  - THP-1 Cells
MH  - Urease/*immunology
OTO - NOTNLM
OT  - H. pylori
OT  - Myh9
OT  - PD-L1
OT  - UreB
OT  - mTORC1
EDAT- 2021/07/24 06:00
MHDA- 2022/02/04 06:00
CRDT- 2021/07/23 12:23
PHST- 2021/06/27 00:00 [received]
PHST- 2021/07/23 00:00 [accepted]
PHST- 2021/07/24 06:00 [pubmed]
PHST- 2022/02/04 06:00 [medline]
PHST- 2021/07/23 12:23 [entrez]
AID - 6326789 [pii]
AID - 10.1093/intimm/dxab044 [doi]
PST - ppublish
SO  - Int Immunol. 2021 Aug 23;33(9):491-504. doi: 10.1093/intimm/dxab044.