title: Enhanced glucocorticoid receptor signaling in T cells impacts thymocyte apoptosis and adaptive immune responses.
abstract: To study the effect of enhanced glucocorticoid signaling on T cells, we generated transgenic rats overexpressing a mutant glucocorticoid receptor with increased ligand affinity in the thymus. We found that this caused massive thymocyte apoptosis at physiological hormone levels, which could be reversed by adrenalectomy. Due to homeostatic proliferation, a considerable number of mature T lymphocytes accumulated in the periphery, responding normally to costimulation but exhibiting a perturbed T-cell repertoire. Furthermore, the transgenic rats showed increased resistance to experimental autoimmune encephalomyelitis, which manifests in a delayed onset and milder disease course, impaired leukocyte infiltration into the central nervous system and a distinct cytokine profile. In contrast, the ability of the transgenic rats to mount an allergic airway response to ovalbumin was not compromised, although isotype switching of antigen-specific immunoglobulins was altered. Collectively, our findings suggest that endogenous glucocorticoids impact T-cell development and favor the selection of Th2- over Th1-dominated adaptive immune responses.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Kirsty G
authors.initials: KG
authors.lastname: McPherson
authors.forename: Katrien L
authors.initials: KL
authors.lastname: de Graaf
authors.forename: Denise
authors.initials: D
authors.lastname: Tischner
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiehr
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.forename: Robert
authors.initials: R
authors.lastname: Weissert
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D015551:Autoimmunity; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D011965:Receptors, Glucocorticoid