Catalase expression mediates redox regulation of promiscuous gene expression in thymic stromal cells

Abstract

Abstract The primary site for the development of T lymphocytes is the thymus, where cross-talk between thymic stromal cells (TSCs) and T cell progenitors mediates the development and maintenance of both populations. However, the thymus begins to atrophy relatively early in life, resulting in diminished T cell output, and corresponding immunodeficiencies in aged individuals. Our previous studies revealed that thymic stromal cells express conspicuously low levels of the peroxide quenching enzyme catalase (CAT), which results in high reactive oxygen species (ROS) levels and accumulated oxidative damage in thymic stromal cells, ultimately promoting thymic atrophy. In our current studies, we find that when catalase deficiency is complemented by overexpression targeted to mitochondria in transgenic mice (mCAT Tg), stromal function declines in young mice relative to non-transgenic littermates. TSC transcriptome analysis reveals decreased expression of tissue-restricted antigen (TRA) genes in young mCat Tg mice relative to controls. Stromal TRA expression is required for self-antigen presentation, and therefore promotes negative selection of potentially auto-reactive T cells. We propose that oxidative stress generated by low catalase levels in stromal cells promotes this key physiological function in the young, steady state thymus; in contrast however, the resulting accumulated oxidative damage ultimately impairs function in the aged thymus.