T-cell-specific Sel1L deletion exacerbates EAE by promoting Th1/Th17-cell differentiation

Area of Science:

• Neuroimmunology
• Cellular Biology
• Protein Quality Control

Background:

• Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory diseases characterized by protein aggregation in the brain.
• The Sel1L-Hrd1 complex, part of the endoplasmic reticulum associated degradation (ERAD) pathway, is crucial for cellular protein quality control (ERQC).
• The specific role of ERAD in T cells during the development of MS and EAE remains largely unexplored.

Purpose of the Study:

• To investigate the role of ERAD, specifically the Sel1L-Hrd1 complex, in T cells during the development of EAE.
• To determine how the conditional deletion of Sel1L in T cells impacts EAE pathogenesis and T cell function.

Main Methods:

• Utilized genetically modified mice with a conditional deletion of Sel1L specifically in T cells.
• Assessed EAE severity in Sel1L knockout (KO) and wild-type (WT) mice.
• Analyzed T cell populations in the thymus and periphery, including CD4 T cell proliferation, differentiation, and apoptosis in vitro.
• Performed RNA sequencing on Sel1L-deficient CD4 T cells to identify gene expression changes.

Main Results:

• Sel1L KO mice exhibited significantly more severe EAE compared to WT controls.
• Increased numbers of CD44-CD25+ double-negative stage 3 (DN3) cells were observed in the thymus of Sel1L KO mice.
• Sel1L deficiency promoted Th1 and Th17 cell differentiation and upregulated CD4 T cell proliferation and apoptosis in vitro.
• RNA sequencing revealed significant alterations in genes related to T cell activation, proliferation, differentiation, and apoptosis in Sel1L-deficient T cells.

Conclusions:

• Dysfunction of Sel1L within the ERAD pathway in T cells exacerbates the severity of EAE.
• The study underscores the critical importance of the ER-protein quality control (ERQC) system in maintaining immune homeostasis within the central nervous system.
• Targeting ERAD in T cells may offer a novel therapeutic strategy for neuroinflammatory diseases like MS.