The glucocorticoid receptor mediates the thymic epithelial cell-induced apoptosis of CD4+8+ thymic lymphoma cells.
"Negative selection" and "death by neglect" are governed by apoptotic processes occurring in the thymus that shape the repertoire of maturing T cells. We have previously developed an in vitro model that recapitulates "death by neglect": Co-cultivation of double positive (DP) thymocytes or thymic lymphoma cells (PD1.6) with thymic epithelial cells (TEC) caused TcR-independent apoptosis of the former. We further demonstrated that this apoptosis could be attenuated by aminoglutethimide, an inhibitor of steroid synthesis, suggesting a role of TEC-derived glucocorticoids (GC) in this death process. We have now substantiated the role of the GC-glucocorticoid receptor (GR) axis by using a GC-resistant subline (PD1.6Dex(-)) obtained from the GC-sensitive PD1.6 cells by repeated exposures to increasing doses of dexamethasone (Dex). The PD1.6Dex(-) cells barely express GR and are much less sensitive to TEC-induced apoptosis. Re-expression of GR in PD1.6Dex(-) cells restored their sensitivity to both Dex and TEC, highlighting the central role of GR in these apoptotic processes. Likewise, repeated exposures of PD1.6 cells to TEC led to the selection of TEC-resistant cells (PD1.6TEC(-)) that are insensitive to corticosterone and less sensitive to Dex, though their GR level was only moderately reduced. This is in line with the low levels of corticosterone secreted by TEC. Altogether, our data show that TEC eliminates DP thymic lymphoma cells in a GR-dependent manner and modulates the GC sensitivity of the surviving cells.
Zilberman
Yael
Y
Department of Pharmacology, Faculty of Dental Medicine Founded by the Alpha-Omega Fraternity, Jerusalem, Israel.
Zafrir
Elazar
E
Ovadia
Haim
H
Yefenof
Eitan
E
Guy
Rina
R
Sionov
Ronit Vogt
RV
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003345:Corticosterone / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D013953:Thymus Neoplasms / Q000276:immunology / Q000378:metabolism*
D015704:CD4 Antigens; D016827:CD8 Antigens; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone; D003345:Corticosterone