Abstract
Autoimmune regulator (Aire) is one of the most crucial genes expressed in the thymus, where it orchestrates the promiscuous expression and presentation of tissue-specific antigens during thymocyte selection. The presence of Aire-expressing cells outside the thymus points toward its plausible extrathymic functions; however, the relative contribution of Aire-expressing cells of hematopoietic origin and their role in the modulation of autoimmune diseases are still obscure. Here, we report that non-obese diabetic mice with transgenic Aire expression under the control of the CD11c (integrin alpha X) promoter were significantly protected from autoimmune diabetes compared with their non-transgenic littermates. The protective effect of Aire transgene was mediated primarily by an increase in the “exhausted” populations of CD4+ and CD8+ T cells, both demonstrating poor expressions of interferon-γ and tumor necrosis factor-α. Both CD4+ and CD8+ effector T cells in transgenic mice displayed distinctive and differential expression of T-bet and Eomesodermin, respectively, in conjunction with high expression of programmed cell death protein-1 and other exhaustion-associated markers. Importantly, transgenic Aire expression did not result in any detectable changes in the population of Foxp3+ regulatory T (Treg) cells. Co-transfer experiments also demonstrated that Aire transgenic dendritic cells, as a “stand-alone” cell population, had the potential to suppress effector T cells in vivo without the support of Treg cells, but eventually failed to prevent the diabetogenesis in recipient mice. In conclusion, our study suggests that apart from its role in clonal deletion of autoreactive T cells or clonal diversion to Treg lineage, Aire can also contribute to tolerance by forcing effector T cells into a state of exhaustion with poor effector functions, thereby effectively containing autoimmune diseases.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease with a very early onset that manifests in genetically susceptible children at less than 10 years of age [1]
Because dendritic cell (DC) play a crucial role in the pathogenesis of autoimmune diabetes, they are a suitable candidate for therapeutic intervention against this disease
IFN-γ was expressed at marginally higher levels in CD4+PD-1hi T cells (Figure 6B). These results suggest that enhanced expression and presentation of tissuespecific antigens (TSAs) by transgenic DCs potentially enforces the exhaustion of cognate effector T cells
Summary
Type 1 diabetes (T1D) is an autoimmune disease with a very early onset that manifests in genetically susceptible children at less than 10 years of age [1]. The epidemiology of T1D shows an uneven global distribution with varying incidences reported from different regions [2] It is primarily a T helper 1 cell-mediated autoimmune disease in which autoreactive T cells selectively destroy pancreatic β cells resulting in insufficient insulin production [3]. Inefficient central tolerance is one of the primary causative factors underlying the pathogenesis of T1D, allowing the selection, and escape of self-reactive T cells from the thymus. Aire is a transcriptional regulator primarily expressed in medullary thymic epithelial cells (mTECs) in the thymus [5] It is responsible for promiscuous expression of a number of peripheral antigens in the mTECs, facilitating their expression, and presentation to cognate thymocytes, failing which may lead to escape of self-reactive T cells from the thymus [6]. Thymic Aire expression can be affected by female sex hormones such as estrogen and progesterone, which may explain why females are at higher risk of developing autoimmune diseases than males in both mice and humans [15]
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