Age-associated changes in central T cell tolerance induction

Abstract

Abstract Susceptibility to certain autoimmune diseases increases with age; however, mechanisms linking aging and increased susceptibility are incompletely understood. One hallmark of the aging immune system is atrophy of the thymus, the primary site of T lymphocyte generation. We and others have previously shown that aging is also associated with declines in critical thymic functions, including expression of tissue restricted self-antigen (TRA) genes, many of which are regulated by the autoimmune regulator, Aire. TRA expression in the thymus allows T cells to be tolerized to antigens typically expressed in peripheral tissues, and declining TRA expression is predicted to contribute to diminished T cell tolerance in aging. Medullary thymic epithelial cells (mTECs) had been regarded as the sole source of thymic TRA expression, but it is now clear that a subset of thymic B (tB) cells also express Aire and mediate tolerance to Aire-dependent self-antigens. Recently, we found that expression of Aire and Aire-dependent self-antigens declines in tB cells in aged mice and humans, which is also predicted to diminish central T cell tolerance induction. To test these predictions, we used MHCII tetramers to detect T cells recognizing a model TRA expressed in mTECs, Apolipoprotein B (Apob, an auto-antigen involved in atherosclerosis), in the thymus and secondary lymphoid organs of aged mice. We find that the frequency of potentially auto-reactive ApoB-specific T cells increases beginning at 6 months of age. Ongoing experiments will address whether there are similar increases in T cells specific for other TRAs, including Titin (Ttn), an autoantigen involved in late onset myasthenia gravis.