PMID- 31480861
OWN - NLM
STAT- MEDLINE
DCOM- 20200526
LR  - 20200831
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 33
IP  - 11
DP  - 2019 Nov
TI  - T-cell-derived extracellular vesicles regulate B-cell IgG production via pyruvate 
      kinase muscle isozyme 2.
PG  - 12780-12799
LID - 10.1096/fj.201900863R [doi]
AB  - Intercellular communication between lymphocytes plays a fundamental role in 
      numerous immune responses. Previously, we demonstrated that hyperhomocysteinemia 
      (HHcy) induced T cell intracellular glycolytic-lipogenic reprogramming and IFN-gamma 
      secretion via pyruvate kinase muscle isozyme 2 (PKM2) to accelerate 
      atherosclerosis. Usually, B cells partially obtain help from T cells in antibody 
      responses. However, whether PKM2 activation in T cells regulates B cell antibody 
      production is unknown. Extracellular vesicles (EVs) are important cellular 
      communication vehicles. Here, we found that PKM2 activator TEPP46-stimulated 
      T-cell-derived EVs promoted B-cell IgG secretion. Conversely, EVs secreted from 
      PKM2-null T cells were internalized into B cells and markedly inhibited B-cell 
      mitochondrial programming, activation, and IgG production. Mechanistically, 
      lipidomics analyses showed that increased ceramides in PKM2-activated T-cell EVs 
      were mainly responsible for enhanced B cell IgG secretion induced by these EVs. 
      Finally, quantum dots (QDs) were packaged with PKM2-null T cell EVs and anti-CD19 
      antibody to exert B-cell targeting and inhibit IgG production, eventually 
      ameliorating HHcy-accelerated atherosclerosis in vivo. Thus, PKM2-mediated EV 
      ceramides in T cells may be an important cargo for T-cell-regulated B cell IgG 
      production, and QD-CD19-PKM2-null T cell EVs hold high potential to treat B cell 
      overactivation-related diseases.-Yang, J., Dang, G., Lu, S., Liu, H., Ma, X., 
      Han, L., Deng, J., Miao, Y., Li, X., Shao, F., Jiang, C., Xu, Q., Wang, X., Feng, 
      J. T-cell-derived extracellular vesicles regulate B-cell IgG production via 
      pyruvate kinase muscle isozyme 2.
FAU - Yang, Juan
AU  - Yang J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Dang, Guohui
AU  - Dang G
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Lu, Silin
AU  - Lu S
AD  - State Key Laboratory of Bioactive Substances and Function of Natural Medicine, 
      Institute of Materia Medica, Peking Union Medical College, Chinese Academy of 
      Medical Sciences, Beijing, China.
FAU - Liu, Huiying
AU  - Liu H
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Ma, Xiaolong
AU  - Ma X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Han, Lulu
AU  - Han L
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Deng, Jiacheng
AU  - Deng J
AD  - Cardiovascular Division, British Heart Foundation (BHF) Centre for Vascular 
      Regeneration, King's College London, London, United Kingdom.
FAU - Miao, Yutong
AU  - Miao Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Li, Xiaopeng
AU  - Li X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Shao, Fangyu
AU  - Shao F
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Jiang, Changtao
AU  - Jiang C
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Xu, Qingbo
AU  - Xu Q
AD  - Cardiovascular Division, British Heart Foundation (BHF) Centre for Vascular 
      Regeneration, King's College London, London, United Kingdom.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
FAU - Feng, Juan
AU  - Feng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry 
      of Education, Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190831
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Immunoglobulin G)
RN  - 0 (Isoenzymes)
RN  - EC 2.7.1.40 (Pkm protein, mouse)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
SB  - IM
MH  - Animals
MH  - *Antibody Formation
MH  - B-Lymphocytes/*immunology/pathology
MH  - Extracellular Vesicles/*immunology/pathology
MH  - Female
MH  - Immune System Diseases/immunology/pathology/therapy
MH  - Immunoglobulin G/*immunology
MH  - Isoenzymes/immunology
MH  - Mice
MH  - Mice, Knockout, ApoE
MH  - Pyruvate Kinase/*immunology
MH  - Quantum Dots
MH  - T-Lymphocytes/*immunology/pathology
PMC - PMC6902684
OTO - NOTNLM
OT  - antibody
OT  - ceramide
OT  - lymphocyte
COIS- The authors are grateful to Prof. Wei Kong (Peking University) for the helpful 
      advice. The authors thank Prof. Shiqiang Wang, Prof. Xuemei Hao, and Prof. 
      Yingchun Hu (Peking University) for assistance with the extracellular vesicle 
      transmission electron microscope assays. This work was supported by the National 
      Natural Science Foundation of China (91739303 and 81770445). The funder of the 
      study had no role in the study design, data collection, data analysis, data 
      interpretation, or writing of the article. The authors were not paid to write 
      this manuscript by a pharmaceutical company or other agency. The authors declare 
      no conflicts of interest.
EDAT- 2019/09/05 06:00
MHDA- 2020/05/27 06:00
PMCR- 2020/08/31
CRDT- 2019/09/05 06:00
PHST- 2019/09/05 06:00 [pubmed]
PHST- 2020/05/27 06:00 [medline]
PHST- 2019/09/05 06:00 [entrez]
PHST- 2020/08/31 00:00 [pmc-release]
AID - FJ_201900863R [pii]
AID - 10.1096/fj.201900863R [doi]
PST - ppublish
SO  - FASEB J. 2019 Nov;33(11):12780-12799. doi: 10.1096/fj.201900863R. Epub 2019 Aug 
      31.