Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus

Glucocorticoids are lipid-soluble hormones that signal via the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Circulating glucocorticoids derive from the adrenals, but it is now apparent that paracrine glucocorticoid signaling occurs in multiple tissues. Effective local gluco...

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Autores principales: Taves, M.D., Mittelstadt, P.R., Presman, D.M., Hager, G.L., Ashwell, J.D.
Formato: JOUR
Materias:
Cyp11b1
glucocorticoid receptor
glucocorticoids
lymphocytes
nuclear receptors
paracrine
steroidogenesis
steroids
transcription factor
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_22111247_v26_n13_p3629_Taves
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
id todo:paper_22111247_v26_n13_p3629_Taves
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spelling todo:paper_22111247_v26_n13_p3629_Taves2023-10-03T16:40:30Z Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus Taves, M.D. Mittelstadt, P.R. Presman, D.M. Hager, G.L. Ashwell, J.D. Cyp11b1 glucocorticoid receptor glucocorticoids lymphocytes nuclear receptors paracrine steroidogenesis steroids transcription factor Glucocorticoids are lipid-soluble hormones that signal via the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Circulating glucocorticoids derive from the adrenals, but it is now apparent that paracrine glucocorticoid signaling occurs in multiple tissues. Effective local glucocorticoid concentrations and whether glucocorticoid delivery can be targeted to specific cell subsets are unknown. We use fluorescence detection of chromatin-associated GRs as biosensors of ligand binding and observe signals corresponding to steroid concentrations over physiological ranges in vitro and in vivo. In the thymus, where thymic epithelial cell (TEC)-synthesized glucocorticoids antagonize negative selection, we find that CD4 + CD8 + TCR hi cells, a small subset responding to self-antigens and undergoing selection, are specific targets of TEC-derived glucocorticoids and are exposed to 3-fold higher levels than other cells. These results demonstrate and quantitate targeted delivery of paracrine glucocorticoids. This approach may be used to assess in situ nuclear receptor signaling in a variety of physiological and pathological contexts. Glucocorticoids signal via the GR, a ligand-dependent transcription factor, and paracrine glucocorticoid signaling occurs in the thymus. Taves et al. use chromatin-associated GRs as biosensors to estimate glucocorticoid concentrations in vitro and in vivo. In the thymus, antigen-signaled CD4 + 8 + TCR hi cells are targeted by epithelial cell-synthesized glucocorticoids to promote positive selection. © 2019 JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_22111247_v26_n13_p3629_Taves
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic Cyp11b1
glucocorticoid receptor
glucocorticoids
lymphocytes
nuclear receptors
paracrine
steroidogenesis
steroids
transcription factor
spellingShingle Cyp11b1
glucocorticoid receptor
glucocorticoids
lymphocytes
nuclear receptors
paracrine
steroidogenesis
steroids
transcription factor
Taves, M.D.
Mittelstadt, P.R.
Presman, D.M.
Hager, G.L.
Ashwell, J.D.
Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus
topic_facet Cyp11b1
glucocorticoid receptor
glucocorticoids
lymphocytes
nuclear receptors
paracrine
steroidogenesis
steroids
transcription factor
description Glucocorticoids are lipid-soluble hormones that signal via the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Circulating glucocorticoids derive from the adrenals, but it is now apparent that paracrine glucocorticoid signaling occurs in multiple tissues. Effective local glucocorticoid concentrations and whether glucocorticoid delivery can be targeted to specific cell subsets are unknown. We use fluorescence detection of chromatin-associated GRs as biosensors of ligand binding and observe signals corresponding to steroid concentrations over physiological ranges in vitro and in vivo. In the thymus, where thymic epithelial cell (TEC)-synthesized glucocorticoids antagonize negative selection, we find that CD4 + CD8 + TCR hi cells, a small subset responding to self-antigens and undergoing selection, are specific targets of TEC-derived glucocorticoids and are exposed to 3-fold higher levels than other cells. These results demonstrate and quantitate targeted delivery of paracrine glucocorticoids. This approach may be used to assess in situ nuclear receptor signaling in a variety of physiological and pathological contexts. Glucocorticoids signal via the GR, a ligand-dependent transcription factor, and paracrine glucocorticoid signaling occurs in the thymus. Taves et al. use chromatin-associated GRs as biosensors to estimate glucocorticoid concentrations in vitro and in vivo. In the thymus, antigen-signaled CD4 + 8 + TCR hi cells are targeted by epithelial cell-synthesized glucocorticoids to promote positive selection. © 2019
format JOUR
author Taves, M.D.
Mittelstadt, P.R.
Presman, D.M.
Hager, G.L.
Ashwell, J.D.
author_facet Taves, M.D.
Mittelstadt, P.R.
Presman, D.M.
Hager, G.L.
Ashwell, J.D.
author_sort Taves, M.D.
title Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus
title_short Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus
title_full Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus
title_fullStr Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus
title_full_unstemmed Single-Cell Resolution and Quantitation of Targeted Glucocorticoid Delivery in the Thymus
title_sort single-cell resolution and quantitation of targeted glucocorticoid delivery in the thymus
url http://hdl.handle.net/20.500.12110/paper_22111247_v26_n13_p3629_Taves
work_keys_str_mv AT tavesmd singlecellresolutionandquantitationoftargetedglucocorticoiddeliveryinthethymus
AT mittelstadtpr singlecellresolutionandquantitationoftargetedglucocorticoiddeliveryinthethymus
AT presmandm singlecellresolutionandquantitationoftargetedglucocorticoiddeliveryinthethymus
AT hagergl singlecellresolutionandquantitationoftargetedglucocorticoiddeliveryinthethymus
AT ashwelljd singlecellresolutionandquantitationoftargetedglucocorticoiddeliveryinthethymus
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