Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Type I interferonopathies are autoimmune diseases driven by chronic nucleic acid sensing.
• Regulatory T cells (Tregs) are crucial for immune homeostasis.
• Mutations in ADAR1 and IFIH1 (MDA5) are linked to type I interferonopathies.

Purpose of the Study:

• To investigate the role of aberrant RNA sensing in Treg dysregulation within type I interferonopathies.
• To elucidate the mechanisms by which ADAR1 and MDA5 impact Treg function and survival.

Main Methods:

• Analysis of patients with type I interferonopathies.
• Murine models with T cell-specific gene modifications (Adar1 deletion, MDA5 gain-of-function).
• Assessment of Treg populations, apoptosis, and autoimmune phenotypes.

Main Results:

• Reduced Tregs observed in patients with ADAR1 or MDA5 mutations.
• Treg-specific Adar1 deletion in mice led to Treg loss and lethal autoimmunity.
• Treg-specific MDA5 gain-of-function in mice caused Treg apoptosis and severe autoimmunity.
• ADAR1 deficiency impacts Tregs through both MDA5 and PKR pathways.

Conclusions:

• Dysregulation of Treg homeostasis by intrinsic aberrant RNA sensing is a key factor in type I interferonopathies.
• ADAR1 and MDA5 play critical roles in maintaining Treg function and preventing autoimmunity.