Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through...

Area of Science:

• Immunology
• Cell Biology
• Extracellular Vesicles

Background:

• Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) possess known immunosuppressive properties.
• T helper 17 (Th17) cells play a critical role in various inflammatory diseases.

Purpose of the Study:

• To elucidate the specific immunosuppressive mechanism of MSC-sEVs on Th17 cells.
• To investigate the role of RAR-related orphan receptor γt (RORγt) in MSC-sEV-mediated immunosuppression.
• To evaluate the therapeutic potential of MSC-sEVs in experimental autoimmune encephalomyelitis (EAE).

Main Methods:

• Treatment of experimental autoimmune encephalomyelitis (EAE) mice with MSC-sEVs.
• Analysis of Th17 cell populations and RORγt protein levels in vivo and in vitro.
• Investigation of MSC-sEVs' effect on RORγt ubiquitination and acetylation.
• Manipulation of EP300-interacting inhibitor of differentiation 3 (Eid3) expression in MSCs and Th17 cells.

Main Results:

• MSC-sEVs convert Th17 cells into IL-17 low-producing (ex-Th17) cells by degrading RORγt protein.
• MSC-sEV treatment ameliorated EAE clinical symptoms and reduced Th17 cell infiltration in lymphoid organs and the CNS.
• MSC-sEVs destabilize RORγt via K63 deubiquitination and deacetylation, mediated by Eid3.
• Eid3 knockdown in MSCs abrogated RORγt downregulation, while Eid3 overexpression decreased RORγt levels in Th17 cells.

Conclusions:

• MSC-sEVs exert immunosuppression by targeting RORγt degradation in Th17 cells through Eid3.
• This novel mechanism highlights MSC-sEVs as a promising therapeutic strategy for Th17-mediated inflammatory diseases.