Targeted Synthesis and Delivery of Steroids from Thymic Epithelial Cells to Developing T cells Drives Immunological Fitness

Adaptive immunity depends on generation of a hugely diverse repertoire of T cell antigen receptors (TCRs). T cells develop in the thymus, where random genetic recombination produces this diverse TCR repertoire, and subsequent testing against self-antigens removes autoreactive T cells that might predispose to autoimmunity. While elevated circulating glucocorticoids (GCs) can cause dramatic thymic atrophy, the thymic epithelial cells express the machinery needed to synthesize GCs de novo from cholesterol. Using a novel technique for single-cell quantification of steroid signaling, we found that locally-synthesized thymic GCs, rather than diffusing throughout the organ, are instead specifically delivered to a rare subset (under 5 percent) of developing T cells after activation of TCR signaling. Unlike systemic GCs, thymic GCs act at this T cell developmental timepoint to counterbalance TCR signaling and protect cells against activation-induced apoptosis. A novel Cyp11b1 reporter mouse and single cell transcriptomic analysis determined that local GC synthesis is orchestrated by Aire, a transcription factor that drives promiscuous expression of thousands of self-antigens and is critical for identification and removal of self-reactive T cells. Aire thus has dual roles in generation of the T cell repertoire - prevention of autoimmunity, but also strengthening and increasing TCR diversity by promoting cell survival. Current work is exploring whether systemic GCs, at low or moderate levels, might also tune the TCR repertoire and have long-lasting effects on risk of autoimmunity, infection, and cancer.

Date of Presentation October 17, 2024