PMID- 31787479
OWN - NLM
STAT- MEDLINE
DCOM- 20210705
LR  - 20210705
IS  - 1095-9157 (Electronic)
IS  - 0896-8411 (Linking)
VI  - 107
DP  - 2020 Feb
TI  - Dendritic cell upregulation of programmed death ligand-1 via DNA demethylation 
      inhibits experimental autoimmune encephalomyelitis.
PG  - 102362
LID - S0896-8411(19)30520-7 [pii]
LID - 10.1016/j.jaut.2019.102362 [doi]
AB  - Dendritic cells (DCs) play key roles in regulating T cell proliferation and 
      differentiation, and epigenetic modification involves in this process. In the 
      periphery, programmed death ligand-1 (PD-L1) expressed on antigen-presenting 
      cells interacts with programmed death-1 (PD-1) on T cells to negatively regulate 
      T cell responses. In this study, we investigate whether DNA demethylation in DCs, 
      downmodulates CD4(+) T cell activation, to halt progression of experimental 
      autoimmune encephalomyelitis (EAE). These results showed that during the 
      development of bone marrow-derived DCs (BMDCs), DNA hypomethylation by 0.1 muM and 
      1 muM 5-aza-2'-deoxycytidine (5-aza) upregulated PD-L1, but not CD40, CD80, or 
      CD86, with surprising downregulation of PD-L2. In co-culture, 5-aza-treated 
      BMDCs, as well as CD11c(+) cells from 5-aza-treated EAE mice, inhibited EAE 
      CD4(+) T cell proliferation and cytokine secretion. Additionally, in vivo 5-aza 
      pretreatment arrested disease progression, inflammatory cell infiltration, and 
      CNS demyelination, in EAE mice. Compared to DCs from vehicle control-treated EAE 
      rodents, DCs from 5-aza-treated EAE mice upregulated PD-L1, in correlation with 
      hypomethylation of the Cd274 promoter. Furthermore, antibody-mediated blockage of 
      PD-L1 rescued EAE progression from 5-aza treatment, in vivo, while also 
      disinhibiting EAE CD4(+) T cell proliferation, by 5-aza-treated DCs, in vitro. 
      Consequently, we conclude that PD-L1 is upregulated via DNA hypomethylation in 
      DCs, resulting in downregulation of autoimmune effector T cell functions, thereby 
      halting progression of EAE.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Chang, Chia-Bin
AU  - Chang CB
AD  - Department of Biomedical Sciences and Institute of Molecular Biology, National 
      Chung-Cheng University, Chia-Yi, Taiwan.
FAU - Lee, Shiao-Pieng
AU  - Lee SP
AD  - Department of Dentistry, Tri-Service General Hospital, Taipei, Taiwan; School of 
      Dentistry, National Defense Medical Center, Taipei, Taiwan.
FAU - Chen, Wei-Ming
AU  - Chen WM
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine, 
      Chang Gung Memorial Hospital, Chia-Yi, Taiwan; Graduate Institute of Clinical 
      Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
FAU - Wang, Chuang-Ming
AU  - Wang CM
AD  - Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian 
      Hospital, Chia-Yi, Taiwan.
FAU - Song, Yu-Chun
AU  - Song YC
AD  - Department of Biomedical Sciences and Institute of Molecular Biology, National 
      Chung-Cheng University, Chia-Yi, Taiwan.
FAU - Chan, Michael W-Y
AU  - Chan MW
AD  - Department of Biomedical Sciences and Institute of Molecular Biology, National 
      Chung-Cheng University, Chia-Yi, Taiwan.
FAU - Wu, Shu-Fen
AU  - Wu SF
AD  - Department of Biomedical Sciences and Institute of Molecular Biology, National 
      Chung-Cheng University, Chia-Yi, Taiwan. Electronic address: biosfw@ccu.edu.tw.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191129
PL  - England
TA  - J Autoimmun
JT  - Journal of autoimmunity
JID - 8812164
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Biomarkers)
RN  - 0 (CD274 protein, human)
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
SB  - IM
MH  - Animals
MH  - B7-H1 Antigen/*genetics/metabolism
MH  - Biomarkers
MH  - Cytokines/metabolism
MH  - *DNA Demethylation
MH  - Dendritic Cells/*immunology/*metabolism
MH  - Disease Models, Animal
MH  - Disease Susceptibility
MH  - Encephalomyelitis, Autoimmune, Experimental/*etiology
MH  - Inflammation Mediators/metabolism
MH  - Lymphocyte Activation/genetics/immunology
MH  - Mice
MH  - T-Lymphocytes/*immunology/*metabolism
OTO - NOTNLM
OT  - 5-aza-2'-deoxycytidine
OT  - CD4(+) T cell activation
OT  - Dendritic cell
OT  - Experimental autoimmune encephalomyelitis
OT  - PD-L1
COIS- Declaration of competing interest The authors declare no conflicts of interest.
EDAT- 2019/12/04 06:00
MHDA- 2021/07/06 06:00
CRDT- 2019/12/03 06:00
PHST- 2019/08/12 00:00 [received]
PHST- 2019/11/04 00:00 [revised]
PHST- 2019/11/06 00:00 [accepted]
PHST- 2019/12/04 06:00 [pubmed]
PHST- 2021/07/06 06:00 [medline]
PHST- 2019/12/03 06:00 [entrez]
AID - S0896-8411(19)30520-7 [pii]
AID - 10.1016/j.jaut.2019.102362 [doi]
PST - ppublish
SO  - J Autoimmun. 2020 Feb;107:102362. doi: 10.1016/j.jaut.2019.102362. Epub 2019 Nov 
      29.