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Review
. 2006 Jan;63(1):60-72.
doi: 10.1007/s00018-005-5390-y.

Glucocorticoids in T cell apoptosis and function

M J Herold  1 , K G McPherson, H M Reichardt
Affiliations
Review

Glucocorticoids in T cell apoptosis and function

M J Herold et al. Cell Mol Life Sci. 2006 Jan.

Abstract

Glucocorticoids (GCs) are a class of steroid hormones which regulate a variety of essential biological functions. The profound anti-inflammatory and immunosuppressive activity of synthetic GCs, combined with their power to induce lymphocyte apoptosis place them among the most commonly prescribed drugs worldwide. Endogenous GCs also exert a wide range of immunomodulatory activities, including the control of T cell homeostasis. Most, if not all of these effects are mediated through the glucocorticoid receptor, a member of the nuclear receptor superfamily. However, the signaling pathways and their cell type specificity remain poorly defined. In this review, we summarize our present knowledge on GC action, the mechanisms employed to induce apoptosis and the currently discussed models of how they may participate in thymocyte development. Although our knowledge in this field has substantially increased during recent years, we are still far from a comprehensive picture of the role that GCs play in T lymphocytes.

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Figures

Figure 1
Figure 1
Molecular modes of GR action. GCs passively diffuse into the cell and bind to the GR (1). This results in the dissociation of the heat shock protein complex (Hsps) (2) and translocation of the ligand-bound GR into the nucleus. There the GR modulates transcription either by binding to DNA (3) or via interaction with other transcription factors (4). Non-genomic mechanisms of GR action include interference with cytosolic signaling molecules (5).
Figure 2
Figure 2
The major pathways of lymphocyte apoptosis. The ‘intrinsic’ pathway involves the activation of ‘BH3-only’ molecules (Bad, Bim etc.) which in turn activate the ‘multidomain’ proteins Bax and Bak. This leads to the formation of the ‘apoptosome’ and activation of caspase-3, a process which is counteracted by the anti-apoptotic proteins Bcl-2 and Bcl-xL. The ‘extrinsic’ pathway is initiated by oligomerization of death receptors followed by caspase-8 activation and also converges on caspase-3. An alternative pathway induced by lysosomal stress involves the release of cathepsins.
Figure 3
Figure 3
Cellular processes involved in GC-induced apoptosis. Bcl- 2 family: transcription of Bim and Puma is upregulated; caspases: caspase-3, -8 and -9 are activated. lysosomes: cathepsin B is released. proteasomal degradation: c-IAP1 and XIAP are degraded at the protein level; H2O2 levels are increased; ceramides are produced, and Na+/ K+ levels altered. The IP3 receptor is engaged. Kinases: PKC, Raf and 14-3-3 proteins interact with the GR.
Figure 4
Figure 4
The role of GCs in thymocyte development. At the double-positive (DP) stage developing thymocytes undergo positive and negative selection which is controlled by an interplay between GR- and T cell receptor (TCR)-derived signals. Mature single-positive (SP) thymocytes are protected from GC-induced apoptosis by CD28 signaling. cTEC, cortical thymic epithelial cell; DC, dendritic cells; mTEC, medullary thymic epithelial cell.
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