Effects of altered glucocorticoid sensitivity in the T‐cell lineage on thymocyte and T‐cell homeostasis

  title={Effects of altered glucocorticoid sensitivity in the T‐cell lineage on thymocyte and T‐cell homeostasis},
  author={Ahmad Pazirandeh and Yi-le Xue and Tore Prestegaard and Mikael Jondal and Sam Okret},
  journal={The FASEB Journal},
The homeostatic regulation that controls total thymocyte and peripheral T‐cell numbers is not clearly understood. We describe here a direct hormonal influence of endogenous levels of glucocorticoids (GCs) on thymocyte and peripheral T‐cell homeostasis independent of indirect systemic effects of GCs. The results were obtained by generating transgenic mice with an altered GC sensitivity targeted to thymocytes and peripheral T cells by increasing or decreasing glucocorticoid receptor (GR… 

Glucocorticoid receptor deficient thymic and peripheral T cells develop normally in adult mice

It is demonstrated that GR signaling is not required for either normal T cell development or peripheral maintenance in embryonic or adult mice, and metyrapone, an inhibitor of glucocorticoid synthesis, impaired thymocytes development regardless of GR genotype indicating that this reagent inhibits thymocyte development in a glucoc Corticoid‐independent fashion.

Conditional expression of a glucocorticoid receptor transgene in thymocytes reveals a role for thymic-derived glucocorticoids in thymopoiesis in vivo.

A role for the thymic-derived GCs in regulating thymocyte homeostasis in vivo is confirmed by conditionally overexpressed the GC receptor (GR) in thymocytes using transgenic mice with a tetracycline-inducible expression system.

The selective impact of transgenically expressed glucocorticoid receptor on T cells

It is concluded that an increased expression of the GR strongly affects numbers and possibly functions of T cell subsets, but has little effect on NK cells.

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

Findings support a model wherein TCR signaling may be required to prevent GC‐induced apoptosis both under basal and immune challenging conditions.

Glucocorticoid Receptor-Deficient Foxp3+ Regulatory T Cells Fail to Control Experimental Inflammatory Bowel Disease

It is suggested that endogenous GC prevent Treg cell plasticity toward a Th1-like Treg Cell phenotype in experimental colitis, and GC-mimicking therapeutic strategies which specifically target Foxp3+ Treg cells for the treatment of inflammatory bowel disease are developed.

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

It is proposed that Tnfaip8 is crucial in regulating glucocorticoid-mediated apoptosis of thymocytes, and downregulating the expression of TnFAip8 alone was sufficient to effectively protectThymocytes against glucoc Corticoid -induced apoptosis.

Glucocorticoids delay age-associated thymic involution through directly affecting the thymocytes.

Novel biological effects of endogenous GCs on thymic involution and T-cell homeostasis in aged mice are revealed, demonstrating that thymocytes and T cells are differentially regulated by GCs.



A Positive Role for Thymus‐Derived Steroids in Formation of the T‐Cell Repertoire

Inhibition of local glucocorticoid biosynthesis in thymi from TCR transgenic mice during fetal thymic organ culture (FTOC) revealed significant alterations in the process of thymocyte selection, suggesting that glucoc Corticoids do not simply suppress the immune system but rather are necessary for thymocytes survival and differentiation.

Glucocorticoids in T cell development and function*.

Based upon in vitro and in vivo studies of T cell development it has been proposed that these locally produced glucocorticoids participate in antigen-specific thymocyte development by inhibiting activation-induced gene transcription and thus increasing the TCR signaling thresholds required to promote positive and negative selection.

Mechanisms of T-cell Apoptosis Induced by Glucocorticoids

  • E. Thompson
  • Biology, Medicine
    Trends in Endocrinology & Metabolism
  • 1999

Glucocorticoids Attenuate T Cell Receptor Signaling

It is demonstrated that dexamethasone, a synthetic GC, inhibits the early signaling events initiated upon TCR ligation, such as tyrosine phosphorylation of several TCR-associated substrates including the ζ chain, the ZAP70 kinase, and the transmembrane adapter molecule linker for activation of T cells.

Glucocorticoid production in the murine thymus

The results of these experiments show that the whole glucocorticoid metabolism takes place within the thymus, which provides the biochemical basis for the in situ effects of glucoc Corticoid hormones on thymocyte development and selection.

T Cell Homeostasis: Thymus Regeneration and Peripheral T Cell Restoration in Mice with a Reduced Fraction of Competent Precursors

It is found that the degree of thymus restoration is determined by the availability of competent precursors and that the number of double-positiveThymus cells is not under homeostatic control.

Apoptosis in human thymocytes after treatment with glucocorticoids

The killing of human thymocytes by dexamethasone was inhibited by cycloheximide, suggesting that this cell death program requires a fully operating protein synthesis machinery and perhaps the induction of new proteins.

Paracrine glucocorticoid activity produced by mouse thymic epithelial cells

It is concluded that TEC secrete a GC hormone activity and a paracrine role for this in thymocyte development is suggested and this is suggested to be a major role in rodents.