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Glucocorticoids (GC) are essential regulators of T-cell development and function. Activation of the immune system increases systemic adrenal-derived GC levels which downregulate immune activity as part of a negative feedback control system. Increasing evidence shows, however, that GC can also be derived from extra-adrenal sources such as the thymus or intestine, thus providing local control of GC-mediated effects. The thymus reportedly produces GC, but whether thymic epithelial cells or thymocytes produce GC acting either in an autocrine or paracrine fashion is not clear. We studied the expression of two main enzymes involved in  de novo  GC synthesis, CYP11A1 and CYP11B1, as well as the expression and activity of HSD11B1, an enzyme catalyzing interconversion of inert GC metabolites with active GC. While we found no evidence of  de novo  GC synthesis in both thymocytes and peripheral T cells, abundant regeneration of GC from the inactive metabolite 11-dehydrocorticosterone was detectable. Irrespective of their maturation stage, T cells that produced GC in this manner undergo autonomous cell death as this was blocked when glucocorticoid receptor-deficient T cells were treated with GC metabolites. These results indicate that both immature and mature T cells possess the capacity to undergo apoptosis in response to intrinsically generated GC. Consequently, positive selection of thymocytes, as well as survival of peripheral T cells may depend on TCR-induced escape of otherwise HSD11B1-driven autonomous T-cell death.

T-cell autonomous death induced by regeneration of inert glucocorticoid metabolites