Browsing by Subject "thymus"
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Item THE AGE-RELATED LOSS OF FOXN1 AND SUBSEQUENT THYMIC INVOLUTION CONTRIBUTES TO AGE-RELATED AUTOIMMUNITY BY ALTERING IMMUNOTOLERANCE(2014-03) Coder, Brandon; Wang, Hongjun; Su, Dong-MingThe thymus is the organ responsible for developing a type of white blood cell called T cells. However, with age comes an increased susceptibility to T cell derived autoimmune disease. Additionally, the thymus progressively shrinks with increased age due to the progressive loss of the gene FoxN1. We want to determine if the loss of FoxN1leads to the thymus being unable to either delete or suppress autoimmune T cells. We utilize a mouse model that has a progressive loss of the FoxN1 gene. Our findings are significant because knowledge gained about the role of the FoxN1 gene with age-related autoimmune disease may lead to novel evidence-based gene therapy that targets the FoxN1 gene to help treat a wide range of autoimmune diseases associated with aging. Purpose (a): The thymus protects against autoimmune disease by generating immunotolernace to self-tissues. This is accomplished through the process of negative selection where self-reactive T cell clones are deleted and also by the generation of natural regulatory T cells (nTregs), which help suppress autoimmunity in the periphery. However, natural aging is associated with thymic atrophy driven by the progressive loss of the gene FoxN1. We wanted to determine if thymic aging impairs immunotolerance, either by disrupting negative selection or altering the generation of suppressive nTreg cells. Methods (b): We answered this question by utilizing a FoxN1 conditional knockout (FoxN1 cKO) mouse model that mimics natural thymic aging through the progressive loss of FoxN1. Results (c): We found that the loss of FoxN1 is associated with the impairment of negative selection characterized by increased single positive T cells and a decrease in Aire+ medullary thymic epithelial cells. Recent thymic emigrants from the FoxN1 cKO thymus have increased proliferation and are more often CD44+, indicating that they are antigen experienced and may be self-reactive T cells. Furthermore, we found that the frequency of nTregs was increased in the FoxN1 cKO thymus, but was normal in the spleen. Additionally, nTregs from the FoxN1 cKO thymus retained normal suppressive function. We adoptively transferred aged wild-type splenocytes, in which there are a higher proportion of Treg cells, into young Rag2-/- mice. We found that the young periphery was able to reverse the accumulation of Tregs. Additionally, the adoptive transfer led to an increase in infiltrating lymphocytes to the salivary gland, which was independent of peripheral age. Conclusions (d): We conclude that the loss of FoxN1 impairs negative selection, which may lead to an escape of self-reactive T cells. However, rather than being cell-intrinsic, the age-related accumulation of Tregs depends on the age of the peripheral microenvironment. These results indicate that the increased susceptibility to autoimmune disease observed with aging is likely due to defects in negative selection rather than changes in nTregs.Item Thymic involution perturbs negative selection and leads to chronic inflammation(2015-08-01) Coder, Brandon D.; Dong-Ming Su; Rance E. Berg; Hriday K. DasThe ubiquitous presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. The etiology of inflammaging is largely unknown. Recent evidence has identified the persistent activation of immune cells, thought to arise from latent viral infections, as key contributors towards the development of a chronic inflammatory environment. However, the contribution of autoreactive T cells towards the development of inflammaging has yet to be investigated. Another pervasive feature of the aging process is the age-related involution of the thymus gland, which has been linked with a predisposition toward developing autoimmunity. In the present study, we determined how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging. We utilized a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics thymic involution while maintaining a young periphery and naturally aged C57Bl/6 mice. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues, elevated serum IL-6, and enhanced production of TNFα. Additionally, activated autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. We determined that a failure of negative selection, facilitated by decreased AIRE expression rather than impaired regulatory T cell (Treg) generation, and led to autoreactive T cell activation in the periphery. Furthermore, we have demonstrated that the young environment can reverse the age-related accumulation of Tregs but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).