Causes and consequences of declining B cell-mediated central T cell tolerance throughout the lifespan

总结

Summary Thymic B cells have recently been shown to express the transcriptional regulator Aire, a critical mediator of TRA expression and T cell tolerance in mice and humans. The only previously known source of intrathymic Aire expression was a subset of medullary epithelial cells (mTECs). Surprisingly, the cohort of genes transcriptionally activated by Aire are almost entirely distinct among B and mTEC, indicating that these populations tolerize T cells to unique cohorts of self-antigens. In a neo-self-antigen/TCR transgenic mouse model, thymic B cells were also shown to mediate tolerance to Aire-dependent self-antigens, however, the role of thymic B cell-mediated central T cell tolerance has not been demonstrated in a physiologically polyclonal system. This is in part due to the technical difficulties associated with the low frequency of T cells specific for a given self-antigen in a polyclonal T cell receptor (TCR) repertoire, and the paucity of thymic B cells and mTECs. Overcoming these obstacles is necessary to understand the mechanisms imposing tolerance to mitigate autoimmunity both in the steady state, and especially during aging. Aging is associated with increased incidence of many autoimmune diseases, and declining thymus function has long been considered an important contributor to age-associated immune dysregulation. Our recent work revealed that Aire expression declines with age in thymic B cells in mice and humans, which would be predicted to diminish tolerance to B cell-specific Aire-dependent self-antigens. However, rigorously testing the mechanistic link between thymic dysfunction and T cell autoimmunity in aging has been hindered because the technical barriers described above are exacerbated in the aged, atrophied thymus. We propose comprehensively testing the hypothesis that age-associated loss of TRA expression in thymic B cells promotes autoimmunity using complementary approaches: tetramer-based enrichment of T cells recognizing endogenous TRAs, and transgenic (Tg) TCR models of tolerance induction to neo self-antigens. Our model endogenous autoantigens, Titin, and Apolipoprotein B, are associated with late-onset Myasthenia Gravis and atherosclerosis, respectively, and we will also employ a Tg TCR model of diabetes (BDC2.5 TCR Tg). We predict that aged thymic B cells will be sufficient to diminish T cell tolerance, and that rescued TRA expression in aged cells will be sufficient to rescue their tolerization potential. We will also comprehensively assess age- associated changes in TEC and tB cells from human thymi to compare age-associated changes in rodents and humans. Together, these data will inform the rational design of strategies to prevent age-associated autoimmunity, potentially revealing novel therapeutic targets.