Aire drives biosynthesis of lipid signal molecules by medullary thymic epithelial cells

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Presentation Time: 09:45 AM - 10:00 AM
Abstract ID: 6046 - B

Presenting Author:
Matthew D Taves , Research Associate at Cornell Univ., NCI, NIH

Abstract:

T cell development in the thymus is supported by thymic epithelial cells (TEC) which play multiple roles in the generation of a competent but self-tolerant repertoire. Self-tolerance is in large part due to medullary TEC (mTEC) expression of the transcription factor Aire, which drives promiscuous gene expression for negative or agonist selection of thymocytes bearing self-reactive T cell antigen receptors. Aire also drives expression of chemokine genes that are necessary for appropriate thymocyte and dendritic cell trafficking and distribution within the thymus. Here, we found that Aire is additionally responsible for expressing biosynthetic pathways of multiple lipid signal molecules that are involved in T cell development. A novel reporter mouse identified Aire+ mTEC cells as the only thymic source of glucocorticoid synthesis, and bulk and single cell transcriptomics demonstrated coexpression of multiple glucocorticoid synthetic enzymes within individual Aire-expressing mTEC. Aire+ mTEC also expressed suites of enzymes needed for production of sex steroids and other lipid signal molecules such as retinoids and prostaglandins, and thymic steroid synthesis was lost in Aire-deficient mice. Aire thus has a novel function driving mTEC generation of steroids and other lipid signals, including some that set thymocyte signaling thresholds for negative selection.