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Glucocorticoid (GC) signaling in thymocytes shapes the TCR repertoire by antagonizing thymocyte negative selection. The transcription factors Nur77 and Helios, which are upregulated in TCR-signaled thymocytes, have been implicated in negative selection. In this study, we found that GCs inhibited Helios and, to a lesser extent, Nur77 upregulation in TCR-stimulated mouse thymocytes. Inhibition was increased by GC preincubation, and reductions in mRNA were prevented by a protein synthesis inhibitor, suggesting that GCs suppress indirectly via an intermediary factor. Upregulation of Helios in TCR-stimulated thymocytes was unaffected by deletion of Nur77, indicating Nur77 and Helios are regulated independently. Whereas CD4 + thymocytes are positively selected in wild-type AND TCR-transgenic B6 mice, loss of GC receptor expression resulted in increased negative selection. Correspondingly, Helios and Nur77 levels were elevated in TCR hi CD4 + CD8 + (TCR-signaled) thymocytes. Notably, deletion of Helios fully reversed this negative selection, whereas deletion of Nur77 had no effect on CD4 + CD8 + cell numbers but reversed the loss of mature CD4 + thymocytes. Thus, Nur77 and Helios are GC targets that play nonredundant roles in setting the signaling threshold for thymocyte negative selection.

Glucocorticoids Oppose Thymocyte Negative Selection by Inhibiting Helios and Nur77