Notch signalling suppresses regulatory T-cell function in murine experimental autoimmune uveitis

Area of Science:

• Immunology
• Ophthalmology
• Cell Biology

Background:

• Autoimmune uveitis is a significant cause of vision loss.
• Understanding immune regulation in the eye is crucial for developing effective treatments.
• Regulatory T-cells (Treg cells) play a key role in immune suppression.

Purpose of the Study:

• To investigate the role of Notch signaling in Treg cell function during experimental autoimmune uveitis (EAU).
• To determine if Notch signaling modulates the immunosuppressive capacity of infiltrating Treg cells in the EAU model.

Main Methods:

• Utilized a mouse model of EAU with Foxp3-GFP reporter mice.
• Analyzed the expression of Notch pathway components (Notch-1, Notch-2, JAG1, DLL1, HES1, HES5) in infiltrating Treg cells.
• Assessed the impact of JAG1 and DLL1 on Treg cell function in vitro.
• Used lentivirus-derived short hairpin RNAs to inhibit Notch signaling in Treg cells before adoptive transfer into EAU mice.

Main Results:

• Infiltrating Treg cells in uveitic eyes expressed Notch pathway components and showed enhanced Notch signaling activation.
• In vitro, JAG1 and DLL1 treatment reduced Foxp3 expression and immunosuppressive activity of Treg cells.
• In vivo, adoptive transfer of Notch-1-deficient Treg cells significantly decreased pro-inflammatory cytokine production and inflammatory cell infiltration in the eyes.

Conclusions:

• Notch signaling negatively modulates the immunosuppressive function of infiltrating Treg cells in experimental autoimmune uveitis.
• Targeting Notch signaling may represent a novel therapeutic strategy for autoimmune uveitis.