Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens

Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function. [Display omitted] •Aging impairs central T cell tolerance induction in the thymus•Decreased autoantigen expression in thymus correlates with increasing autoreactivity•Catalase expression mitigates age-associated waning of flu-specific T cells•Redox status effect on T cell selection varies across TCR specificities Age-associated thymic dysfunctions increase susceptibility to infection by diminishing T cell generation and may also impair T cell tolerance. Hester et al. demonstrate age-associated declines in tolerance induction, including impaired tolerance to an atherosclerosis autoantigen. Catalase overexpression delays thymic atrophy and mitigates declines in influenza-specific T cells, but does not rescue impaired central tolerance.