Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation

Area of Science:

• Immunology
• Aging Research
• Inflammation Biology

Background:

• Thymic involution and autoreactive T cell release are linked to autoimmunity.
• Chronic low-level inflammation (inflammaging) is a risk factor for age-related diseases.

Purpose of the Study:

• To investigate how thymic involution drives persistent autoreactive T cell activation and inflammaging.
• To determine the mechanisms underlying autoreactive T cell generation during thymic aging.

Main Methods:

• Utilized a Foxn1 conditional knockout mouse model for accelerated thymic involution.
• Analyzed T cell activation, phenotype, and autoreactivity in young and aged mice.
• Assessed the role of Aire expression and regulatory T cells in negative selection failure.

Main Results:

• Accelerated thymic involution induced T cell activation and a chronic inflammatory phenotype.
• Detected autoreactive T cell clones and increased pro-inflammatory cytokines (TNF-α, IL-6).
• Identified decreased Aire expression as the cause of failed negative selection, not impaired regulatory T cells.

Conclusions:

• Thymic involution contributes to inflammaging through persistent autoreactive T cell activation.
• Failed negative selection due to reduced Aire expression is a key mechanism.
• While a young environment can reverse Treg accumulation, it does not resolve inflammatory infiltration.