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EMBO J. 2018 Aug 15;37(16). pii: e99429. doi: 10.15252/embj.201899429. Epub 2018 Jul 26.

Targeting prohibitins at the cell surface prevents Th17-mediated autoimmunity.

Author information

1
Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
2
Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
3
Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
4
Cancer Cell Biology and Drug Discovery Group, Life Sciences Research Unit University of Luxembourg, Esch-sur-Alzette, Luxembourg.
5
Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
6
Department of Biosciences, University of Oslo, Oslo, Norway.
7
Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany frauke.zipp@unimedizin-mainz.de krishna@uni-mainz.de.
8
Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany frauke.zipp@unimedizin-mainz.de krishna@uni-mainz.de.

Abstract

T helper (Th)17 cells represent a unique subset of CD4+ T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in orchestrating autoimmunity. By employing quantitative surface proteomics, we found that the evolutionarily conserved prohibitins (PHB1/2) are highly expressed on the surface of both murine and human Th17 cells. Increased expression of PHBs at the cell surface contributed to enhanced CRAF/MAPK activation in Th17 cells. Targeting surface-expressed PHBs on Th17 cells with ligands such as Vi polysaccharide (Typhim vaccine) inhibited CRAF-MAPK pathway, reduced interleukin (IL)-17 expression and ameliorated disease pathology with an increase in FOXP3+-expressing Tregs in an animal model for multiple sclerosis (MS). Interestingly, we detected a CD4+ T cell population with high PHB1 surface expression in blood samples from MS patients in comparison with age- and sex-matched healthy subjects. Our observations suggest a pivotal role for the PHB-CRAF-MAPK signalling axis in regulating the polarization and pathogenicity of Th17 cells and unveil druggable targets in autoimmune disorders such as MS.

KEYWORDS:

CRAF; FOXP3; MAPK; multiple sclerosis; prohibitins

PMID:
30049713
PMCID:
PMC6092617
[Available on 2019-08-15]
DOI:
10.15252/embj.201899429

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