Steroid production in the thymus: implications for thymocyte selection.

Abstract

SummaryThe mouse thymus was assessed for its ability to produce steroids. Cultured thymic non-T cells produced soluble pregnenolone and deoxycorticosterone, and immunohistochemistry demonstrated steroidogenic enzymes in radioresistant thymic epithelial cells but not in thymocytes. Inhibition of thymic corticosterone production or blockade of the ghcocorticoid receptor with RU-486 resulted in enhanced TCR-mediated, antigen-specific deletion of immature thymocytes. These data indicate that locally produced glucocorticoids, because of their antagonism of TCR-mediated signaling for death, may be a key element of antigen-specific thymocyte sdection.

p53 and thymic ‘death by neglect’: thymic epithelial cell-induced apoptosis of CD4+8+ thymocytes is p53-independent

“…10 GC may be secreted by TEC, which possess all the enzymes required for their biosynthesis. 8 Our data, however, suggested that GC is not the sole mediator and that TEC deliver additional, as yet unidentified signals, which participate in apoptosis of DP cells 10 (and unpublished data).…”

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development

“…Conversely, removal of endogenous GC by adrenalectomy leads to hypertrophy of the thymus [18] and spleen [19]. In addition to the adrenals, we and others have identified the thymus as a site of GC production [20][21][22][23]. A physiological role of GC in T cell development and selection is implied by the observation that TCR and glucocorticoid receptor (GR) signaling demonstrate crosstalk.…”

Colon cancer cells produce immunoregulatory glucocorticoids

“…The adrenal glands are the major source of GC in the body. However, different reports indicate that GC synthesis is not restricted to the adrenal glands but may also occur at other sites of the body (Noti et al, 2009), for example, the thymus (Vacchio et al, 1994), the brain (MacKenzie et al, 2000;Davies and MacKenzie, 2003) and the vascular endothelium (Takeda et al, 1994). Recently, we have characterized the intestinal epithelium as a major source of immunoregulatory GC (Cima et al, 2004;Mueller et al, 2006Mueller et al, , 2007Atanasov et al, 2008).…”

“…It develops through a series of genetic mutations in pluripotent stem cells in the intestinal epithelial crypts (Davies et al, 2005). Many cancer cells aberrantly overexpress cellular proteins or neo-antigens, which can be recognized by the immune system and provoke anti-tumor immune responses (van den Broek et al, 1996;Smyth et al, 2000;Shankaran et al, 2001). Also, CRC cells are often immunogenic and can stimulate the activation of tumor-specific lymphocytes (Camus et al, 2009).…”