Impact of age-associated decreases in thymic B cell expression of Aire and self-antigen genes on T cell tolerance

Abstract

Abstract Susceptibility to many autoimmune diseases increases with age, but the mechanisms linking aging and autoimmunity remain incompletely understood. One hallmark of the aging immune system is atrophy of the thymus, the primary site of T lymphocyte generation and tolerance induction. Aging is also associated with declines in critical thymic functions, including expression of tissue restricted self-antigen (TRA) genes important in tolerance induction. We have focused on a subset of TRAs transcribed preferentially by thymic B cells under control of the Autoimmune regulator (Aire). This expression results in clonal deletion (tolerization) of T cells specific for these antigens which are typically expressed in peripheral tissues. Recently, we found that expression of both Aire and Aire-dependent TRA genes in thymic B cells declines with aging in both mice and humans, leading to the prediction that central T cell tolerance to B cell TRAs would be diminished in older individuals. As a direct test of this hypothesis, splenic B cells from young and aged AdBDC transgenic mice (present an Aire-regulated BDC2.5 antigen) were transferred into irradiated hosts reconstituted with BDC2.5 TCR transgenic bone marrow. We find that aging diminishes the capacity of AdBDC B cells to mediate clonal deletion of cognate BDC2.5 T cells. We also used MHCII tetramers and ELISpot to detect T cells recognizing a model TRA expressed in thymic B cells, Titin (Ttn), an auto-antigen involved in late-onset myasthenia gravis, in the thymus and secondary lymphoid organs of young and aged mice. Together, our preliminary results suggest that the reduced capacity of aged thymic B cells to express Aire also impairs their ability to properly tolerize developing T cells in the thymus.