Redox regulation of autophagy in thymic stromal cell function

Abstract

Abstract T lymphocytes develop in the thymus, where mutually inductive signaling between lymphoid progenitors and thymic stromal cells directs the progenitors along a well-characterized program of differentiation. However, the biology of the stromal cells comprising the lymphopoietic thymic microenvironment remains relatively under-characterized because stromal cells are rare and difficult to isolate. Using a deconvolution technique to study gene expression essentially in situ, we previously identified a deficiency in the peroxide quenching enzyme catalase (CAT) in thymic stromal cells, and found that CAT deficiency results in high reactive oxygen (ROS) levels in this population, eventually leading to thymic atrophy. Our current studies address the possibility that high ROS levels serve physiological functions in stromal cells in the young, steady-state thymus. Autophagy is critical for self-antigen presentation and T cell selection in the thymus, and is induced by many stressors, including oxidative stress. Our preliminary data indicate that catalase overexpression targeted to mitochondria in transgenic mice (mCAT Tg) results in diminished autophagy in thymic stromal cells and causes diminished negative selection in the thymus. Our results suggest that, while accumulated oxidative damage ultimately undermines healthy thymus function, a high ROS environment in stromal cells promotes autophagy critical for stromal induction of T cell tolerance in the young, steady-state thymus. Supported by N.I.H. grants R01AI121367 and R21AI103685