Impact of age-associated decrease in thymic B cell expression of Aire and self-antigen genes on T cell tolerance
| Autor: | Sergio Cepeda, Yangming Xiao, Ellen Kraig, Ann Griffith |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 204:143.2-143.2 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Susceptibility to many autoimmune diseases increases with age, however, mechanisms linking aging and susceptibility to 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, 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. Until recently, medullary thymic epithelial cells (mTECs) were the only known 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. We found that expression of Aire and Aire-dependent self-antigens declines in tB from aged mice and humans, which is likewise predicted to diminish central T cell tolerance induction. To test these predictions, we used I-Ab MHCII tetramers to detect T cells recognizing a model TRA expressed in tB cells, Titin (Ttn, an auto-antigen associated with late-onset myasthenia gravis), in the thymus and secondary lymphoid organs (SLO) of young and aged mice. We find an increase in potentially auto-reactive Ttn-specific T cells in SLO of aged mice, concomitant with declining Ttn expression in tB cells. Ongoing experiments will compare the capacity of young and aged thymic B cells to tolerize T cells using the BDC2.5 TCR- and Aire-driven BDC peptide-transgenic mouse models. |
| Databáze: | OpenAIRE |
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