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Department of Biochemistry and Molecular Biology (T.J.C., D.R.L.), Monash University, Clayton, Victoria 3800, Australia; and Department of Microbiology and Immunology (D.R.L., D.I.G.), University of Melbourne, Parkville, Victoria 3010, Australia
Address all correspondence and requests for reprints to: T. J. Cole, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. E-mail: tim.cole{at}med.monash.edu.au.
It is well accepted that T cells, particularly immature thymocytes, are very sensitive to glucocorticoids, with an elevation of glucocorticoid levels during stress causing profound involution of the thymus (1). Despite this, the significance of glucocorticoids in thymocyte development and function remains an unclear and controversial area. A report in this issue of Endocrinology (2) has again turned the spotlight on the potential importance of glucocorticoids synthesized by the thymus, most likely arising from thymic epithelial cells. The authors present results of a study where a conditional rat glucocorticoid receptor (GR) transgene has been specifically expressed in mouse T cells using the tetracycline-inducible expression system with a human T cell-specific CD2 (hCD2) promoter. They show that in adrenalectomized (to exclude systemic glucocorticoids) transgenic mice, there is a dramatic increase in thymocyte death by apoptosis after doxycycline-induction of the GR transgene, implicating induction of T-cell death from endogenously produced glucocorticoids. This was replicated in vitro using a thymic organ culture system and the increased death in vivo and in vitro could be at least partially blocked by the GR antagonist RU486. These results give compelling evidence for the presence of thymic-produced glucocorticoids that, at least in this transgenic system, are able to trigger significant thymocyte apoptosis. This clearly supports the concept that the thymus is a source of functionally significant levels of glucocorticoid hormone, although a number of unanswered questions remain.
Several papers have reported the presence or production of endogenous glucocorticoids in the thymus, most likely by thymic stromal cells (3, 4, 5, 6, 7, 8, 9). The synthesis of glucocorticoids in the thymus was initially suggested in studies using in vitro fetal thymic organ culture with the use of selective inhibitors of corticosteroid biosynthesis, such as metyrapone (3, 4, 5, 6). The capacity of the thymus to synthesize endogenous glucocorticoids was then suggested by the detection of the complement of glucocorticoid biosynthetic enzyme genes in the mouse and chicken thymus by RT-PCR, and chromatographic analysis of steroid production from thymus and thymic epithelial cell line extracts, although enzymatic activities in comparison to the adrenal were low (7, 8). Blockade of glucocorticoid production in the thymus appeared to cause deletion of CD4+CD8+ thymocytes. These studies suggested that GR signaling influenced T-cell receptor (TCR)-mediated antigen-specific thymocyte development and survival, primarily by antagonizing TCR signaling and thereby inhibiting TCR-dependent thymocyte deletion. This hypothesis was subsequently supported by other studies using GR antisense transgenic mice to reduce GR expression (10). In each case, reduced GR signaling resulted in reduced thymocyte numbers, suggesting that physiological levels of GR signaling is an important factor in thymocyte survival, associated with intrathymic-positive selection (11).
Despite this compelling evidence from multiple models, other groups with different models have failed to generate data to support a role for glucocorticoids in promoting thymocyte survival. Some other studies have suggested that glucocorticoids promote thymocyte death and that blockade of glucocorticoid signaling enhances survival, whereas others, using GR knockout or mutant mice, have failed to show an influence of glucocorticoid signaling on thymocyte development, selection, or survival (12, 13, 14, 15, 16). Clearly this remains an area of ongoing controversy that requires further investigation (17, 18, 19, 20, 21, 22, 23). Although the precise influence of glucocorticoid hormones in the thymus remains unclear, the exquisite sensitivity of thymocytes to glucocorticoids, and the constitutive production of glucocorticoid hormones in this tissue, strongly suggests that this signaling pathway can at least potentially play a role in T-cell development. This is obvious at times of stress, where glucocorticoid levels increase leading to massive thymocyte apoptosis (1), and it is possible that glucocorticoids might normally play a more subtle role in the thymus that is not always detectable or reproducible across different mouse models of T-cell development. For example, glucocorticoids have recently been showed to strongly activate the IL7-R-
-chain on T cells, and endogenous glucocorticoids may play a regulatory role in this activation (24).
The present study using adrenalectomized T cell-specific-inducible GR transgenic mice implicates the action of endogenously produced glucocorticoids in thymocyte survival. This is a very interesting result that raises some new and important questions. Does this reflect a physiological response to thymus-derived glucocorticoid levels? This obviously depends on the relative level of GR expression from the transgenic insert, compared with endogenous wild-type GR levels. This was not directly compared in this study but would provide valuable information to help interpret these data. One experiment in this study (see Fig. 5 in Ref. 2) appears to show that thymus-derived glucocorticoids are responsible for reduced thymocyte numbers even when the GR transgene is not induced by doxycycline. Treatment of adrenalectomized hCD2-GR transgenic mice (apparently without doxycycline-mediated induction of this transgene) with the GR antagonist RU486 resulted in increased thymocyte numbers. This is perhaps the best evidence for a physiological role for thymic-derived glucocorticoid production in controlling thymocyte numbers in vivo. However, whether a similar result would be achieved in nontransgenic mice remains unknown but would seem to be an important experiment in this context. Other interesting questions raised by this study include how active is the glucocorticoid biosynthetic pathway in the thymus and whether it undergoes hypothalamic-pituitary regulatory control, similar to the adrenal cortex.
In summary, this study provides further evidence for the production of intrathymic glucocorticoids. Although this does not resolve the ongoing controversy surrounding the precise function of glucocorticoids in intrathymic T-cell development, it reemphasizes the fact that glucocorticoids are produced in the thymus at functionally significant levels, which restates the question of the role of intrathymic glucocorticoid production. Determination of the response from non-GR transgenic T cells to thymus-derived glucocorticoid production is clearly an important step toward appreciating the physiological significance of the results presented in these GR transgenic mice. Such homeostatic roles may, however, be overwhelmed during times of systemic stress because high levels of adrenal-derived glucocorticoids flood the thymus and bring about classic thymocyte death and thymic involution. The endocrine community waits with great interest for further results and details on intrathymic glucocorticoid production, and its physiological role in T-cell homeostasis and development.
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Received March 3, 2005.
Accepted for publication March 18, 2005.
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. J Immunol 168:2212–2218This article has been cited by other articles:
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  M. Heikenwalder, M. Prinz, N. Zeller, K. S. Lang, T. Junt, S. Rossi, A. Tumanov, H. Schmidt, J. Priller, L. Flatz, et al. Overexpression of Lymphotoxin in T Cells Induces Fulminant Thymic Involution Am. J. Pathol., June 1, 2008; 172(6): 1555 - 1570. [Abstract] [Full Text] [PDF]
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 S. NEGRINI, D. FENOGLIO, P. BALESTRA, M. FRAVEGA, G. FILACI, and F. INDIVERI Endocrine Regulation of Suppressor Lymphocytes: Role of the Glucocorticoid-Induced TNF-Like Receptor Ann. N.Y. Acad. Sci., June 1, 2006; 1069(1): 377 - 385. [Abstract] [Full Text] [PDF]
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