Central tolerance is impaired in the middle-aged thymic environment

Area of Science:

• Immunology
• Aging Research
• T-cell Biology

Background:

• Thymus involution is an early sign of immune aging, impacting T-cell production and the thymus microenvironment.
• While T-cell export continues into adulthood, the effect of thymus involution on the quality of new T-cell clones and central tolerance is not fully understood.

Purpose of the Study:

• To investigate the impact of thymus involution on thymocyte motility, central tolerance induction, and the associated changes in the thymus microenvironment.
• To determine how age-associated alterations in the thymus affect the selection of T cells, particularly concerning self-antigens of varying avidity.

Main Methods:

• Utilized thymic slice assays to assess thymocyte motility and interactions with antigen-presenting cells (APCs) in middle-aged versus young thymic environments.
• Examined the efficiency of negative selection and regulatory T-cell (Treg) induction for thymocytes responding to tissue-restricted antigens (TRAs) and ubiquitous self-antigens.

Main Results:

• The middle-aged thymus environment restricts medullary thymocyte motility, potentially hindering their interaction with APCs presenting self-antigens.
• Central tolerance induction, including negative selection and Treg generation, is impaired in middle age, especially for self-antigens with moderate avidity or lower expression.
• Age-associated reductions in medullary thymic epithelial cells (mTECs) and specific hematopoietic APC subsets correlate with the decline in central tolerance.

Conclusions:

• Age-related changes in the thymus microenvironment lead to impaired central tolerance against moderate-avidity self-antigens.
• Middle-aged individuals may export a higher proportion of autoreactive naive T cells and a reduced number of regulatory T cells, compromising immune homeostasis.