Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms

Area of Science:

• Immunology
• Autoimmunity
• Endocrinology

Background:

• Autoimmune diseases arise from failures in immune tolerance, specifically thymic T cell elimination and peripheral T cell activation.
• The precise roles of thymic and peripheral tolerance mechanisms in disease development remain incompletely understood.

Purpose of the Study:

• To investigate the impact of manipulating immune tolerance checkpoints on tissue-specific autoimmunity using a model of type I diabetes.
• To determine how human AIRE (huAIRE) expression in different immune compartments affects autoimmune disease development.

Main Methods:

• NOD mice, a model for type I diabetes, were engineered to express huAIRE in the thymic stroma and/or peripheral antigen-presenting cells (APCs).
• Immune tolerance function, T cell populations, and autoimmune disease incidence were assessed.
• The role of Xcr1+ dendritic cells in peripheral tolerance was examined.

Main Results:

• huAIRE expression in the thymic stroma did not significantly alter diabetogenic T cell production.
• huAIRE expression in peripheral APCs conferred resistance to type I diabetes by reducing Xcr1+ dendritic cells, crucial for diabetogenic T cell activation.
• This peripheral intervention preserved other autoimmune responses and antibody production against foreign antigens.
• Contrasting findings were observed with combined thymic and peripheral huAIRE expression, leading to muscle-specific autoimmunity.

Conclusions:

• Tissue-specific autoimmunity is differentially regulated by a combination of thymic and peripheral tolerance mechanisms.
• The expression of huAIRE/Aire can be strategically manipulated in distinct immune compartments to modulate autoimmune disease outcomes.
• Peripheral tolerance, particularly involving Xcr1+ dendritic cells, plays a critical role in preventing type I diabetes.