Aire Drives Steroid Hormone Biosynthesis by Medullary Thymic Epithelial Cells

• Published in: The Journal of immunology (1950) Vol. 210; no. 1_Supplement; pp. 219 - 219.12
• Main Authors: Donahue, Kaitlynn, Taves, Matthew, Ashwell, Jonathan D
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.219.12

Abstract Thymocytes progress toward mature T cells through a series of antigen-specific selection steps facilitated by thymic epithelial cells (TECs) in the cortex, the site of positive selection, and medulla, the site of negative selection. TECs produce glucocorticoids (GCs), which enhance positive selection and increase the fitness of the T cell antigen-specific repertoire, but which TEC subpopultion does this, and how it is regulated, is unknown. We generated a reporter mouse that expresses a fusion protein containing Cyp11b1, the enzyme that mediates the last step in de novoGC production, and the fluorescent tag mScarlet knocked into the endogenous Cyp11b1locus. We found that Cyp11b1 is exclusively expressed in medullary TECs (mTECs), consistent with the notion that GC antagonize negative selection. This is seemingly at odds with the fact that mTECs facilitate negative selection via the transcription factor Aire, which drives promiscuous expression of tissue-restricted antigens (TRAs) vital for establishing central immune tolerance. We found that Cyp11b1 is primarily expressed in Aire+ and post-Aire mTECs and is absent in mTECs of Aire-deficient mice. Transcriptomic analysis showed that most genes of the GC biosynthetic pathway are expressed in mTECs in an Aire-dependent manor. Moreover, we found that their actual steroid product was produced by WT but not Aire-deficient thymi. We propose that in addition to its well-established role of inducing TRAs that promote negative selection, Aire has an obverse function in inducing production of GC that antagonize negative selection, which together expand and enhance the TCR repertoire.