Targeting prohibitins at the cell surface prevents Th17‐mediated autoimmunity

• Published in: The EMBO journal Vol. 37; no. 16
• Main Authors: Buehler, Ulrike, Schulenburg, Katharina, Yurugi, Hajime, Šolman, Maja, Abankwa, Daniel, Ulges, Alexander, Tenzer, Stefan, Bopp, Tobias, Thiede, Bernd, Zipp, Frauke, Rajalingam, Krishnaraj
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.08.2018; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Activation; Animal models; Animals; Autoimmune diseases; Autoimmunity; CD4 antigen; Cell surface; CRAF; Differentiation; EMBO19; Extracellular Signal-Regulated MAP Kinases - immunology; Forkhead Transcription Factors - immunology; FOXP3; Foxp3 protein; Fungi; HeLa Cells; Helper cells; Humans; Interleukins; Ligands; Lymphocytes; Lymphocytes T; MAP kinase; MAPK; Mice; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Pathogenicity; Pathogens; Patients; Polarization; Polysaccharides; prohibitins; Proteomics; Repressor Proteins - immunology; Rickettsial Vaccines - pharmacology; Signal transduction; Signal Transduction - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Th17 Cells - immunology; Th17 Cells - pathology; CRAF; MAPK; FOXP3; multiple sclerosis; prohibitins
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201899429

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. Synopsis Prohibitins are highly expressed on the surface of Th17 cells contributing to high CRAF‐MAPK activation and polarization. Employment of PHB ligands inhibits CRAF activation and impairs Th17 mediated pathogenicity. Surface expressed prohibitins (PHBs) regulate Th17 differentiation. Prohibitins (PHBs) are highly expressed on the surface of Th17 cells contributing to enhanced CRAF kinase activation. Targeting surface‐expressed PHBs inhibited the CRAF–MAPK pathway and Th17 differentiation and promoted expression of FOXP3. PHBs are highly surface expressed in a subset of CD4 + T cells from patients suffering from multiple sclerosis. Graphical Abstract Prohibitins are expressed on the surface of Th17 cells and regulate CRAF‐MAPK activation, polarization and pathogenicity of Th17 cells.