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

Lourdes Rocamora-Reverte,Gjan Wiegers,Andreas Villunger,Holger M Reichardt

doi:10.1038/cddis.2017.344

Abstract

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.

Highlights

Glucocorticoids (GC) are steroid hormones primarily produced in the adrenal cortex in response to emotional, physical and immunological stress
Expression analysis of glucocorticoid metabolic enzymes across T-cell development. To date it is unclear which cell type(s) of the thymus are responsible for GC synthesis (Figure 1a), being TEC and/or thymocytes a matter of debate
To unravel the origin of thymus-derived GC production, we studied the expression of two critical steroidogenic enzymes in T cells at different developmental stages, from immature thymocytes to mature peripheral T cells in the spleen (Table 1)

Summary

Introduction

Glucocorticoids (GC) are steroid hormones primarily produced in the adrenal cortex in response to emotional, physical and immunological stress. Immature double-negative (DN) thymocytes (CD4 − CD8 − ) proliferate and differentiate in the thymus to generate double-positive (DP) CD4+CD8+ cells. While the main source of GC are the adrenals, evidence accumulated over the last two decades that GC are de novo synthesized in other organs including the brain, intestinal tract, skin and thymus (both epithelial and immune cells).[14,15]. These organs express the steroidogenic enzymes necessary for the synthesis of GC which apparently act in an autocrine or paracrine fashion.[3] Overexpression of GR in the. T-cell lineage leads to a reduced number of thymocytes in adrenalectomized mice, suggesting that non-adrenal-derived GC could exert a negative effect on thymocyte development.[16]

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