J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/06/2033/06 $2.00
Volume 185, Number 11, June 2, 1997 2033-2038

BRIEF DEFINITIVE REPORT:
Thymus-derived Glucocorticoids Regulate Antigen-specific Positive Selection

By Melanie S. Vacchio,^* and Jonathan D. Ashwell

From the ^* Laboratory of Immunology, Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20852; and  Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1152

While it is generally believed that the avidity of the T cell antigen receptor (TCR) for self antigen/major histocompatibility complex (MHC) determines a thymocyte's fate, how the cell discriminates between a stimulus that causes positive selection (survival) and one that causes negative selection (death) is unknown. We have previously demonstrated that glucocorticoids are produced in the thymus, and that they antagonize deletion caused by TCR cross-linking. To examine the role of glucocorticoids during MHC-dependent selection, we examined thymocyte development in organ cultures in which corticosteroid biosynthesis was inhibited. Inhibition of glucocorticoid production in thymi from /-TCR transgenic mice resulted in the antigen- and MHC-specific loss of thymocytes that normally recognize self antigen/MHC with sufficient avidity to result in positive selection. Furthermore, inhibition of glucocorticoid production caused an increase in apoptosis only in CD⁺CD8⁺ thymocytes bearing transgenic TCRs that recognized self antigen/MHC. These results indicate that the balance of TCR and glucocorticoid receptor signaling influences the antigen-specific thymocyte development by allowing cells with low-to-moderate avidity for self antigen/MHC to survive.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• D'Elia, M., Patenaude, J., Bernier, J. (2009). Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice. Am. J. Physiol. Endocrinol. Metab. 296: E97-E104 [Abstract] [Full Text]  
• Schmidt, K. L., Soma, K. K. (2008). Cortisol and corticosterone in the songbird immune and nervous systems: local vs. systemic levels during development. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295: R103-R110 [Abstract] [Full Text]  
• Aeberli, D., Leech, M., Morand, E. F. (2006). Macrophage migration inhibitory factor and glucocorticoid sensitivity. Rheumatology (Oxford) 45: 937-943 [Abstract] [Full Text]  
• Cole, T. J., Liddicoat, D. R., Godfrey, D. I. (2005). Intrathymic Glucocorticoid Production and Thymocyte Survival: Another Piece in the Puzzle. Endocrinology 146: 2499-2500 [Full Text]  
• Igarashi, H., Medina, K. L., Yokota, T., Rossi, M. I. D., Sakaguchi, N., Comp, P. C., Kincade, P. W. (2005). Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids. Int Immunol 17: 501-511 [Abstract] [Full Text]  
• Zhang, T. Y., Ding, X., Daynes, R. A. (2005). The Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type I by Lymphocytes Provides a Novel Means for Intracrine Regulation of Glucocorticoid Activities. J. Immunol. 174: 879-889 [Abstract] [Full Text]  
• Cima, I., Corazza, N., Dick, B., Fuhrer, A., Herren, S., Jakob, S., Ayuni, E., Mueller, C., Brunner, T. (2004). Intestinal Epithelial Cells Synthesize Glucocorticoids and Regulate T Cell Activation. JEM 200: 1635-1646 [Abstract] [Full Text]  
• Ko, M., Jang, J., Ahn, J., Lee, K., Chung, H., Jeon, S. H., Seong, R. H. (2004). T Cell Receptor Signaling Inhibits Glucocorticoid-induced Apoptosis by Repressing the SRG3 Expression via Ras Activation. J. Biol. Chem. 279: 21903-21915 [Abstract] [Full Text]  
• Stephens, G. L., Ashwell, J. D., Ignatowicz, L. (2003). Mutually antagonistic signals regulate selection of the T cell repertoire. Int Immunol 15: 623-632 [Abstract] [Full Text]  
• Liu, X., Adams, A., Wildt, K. F., Aronow, B., Feigenbaum, L., Bosselut, R. (2003). Restricting Zap70 Expression to CD4+CD8+ Thymocytes Reveals a T Cell Receptor-dependent Proofreading Mechanism Controlling the Completion of Positive Selection. JEM 197: 363-373 [Abstract] [Full Text]  
• Spinetti, G., Bernardini, G., Camarda, G., Mangoni, A., Santoni, A., Capogrossi, M. C., Napolitano, M. (2003). The chemokine receptor CCR8 mediates rescue from dexamethasone-induced apoptosis via an ERK-dependent pathway. J. Leukoc. Biol. 73: 201-207 [Abstract] [Full Text]  
• Brewer, J. A., Kanagawa, O., Sleckman, B. P., Muglia, L. J. (2002). Thymocyte Apoptosis Induced by T Cell Activation Is Mediated by Glucocorticoids In Vivo. J. Immunol. 169: 1837-1843 [Abstract] [Full Text]  
• Brewer, J. A., Sleckman, B. P., Swat, W., Muglia, L. J. (2002). Green Fluorescent Protein-Glucocorticoid Receptor Knockin Mice Reveal Dynamic Receptor Modulation During Thymocyte Development. J. Immunol. 169: 1309-1318 [Abstract] [Full Text]  
• Yu, C.-T., Feng, M.-H. L., Shih, H.-m., Lai, M.-Z. (2002). Increased p300 Expression Inhibits Glucocorticoid Receptor-T-Cell Receptor Antagonism but Does Not Affect Thymocyte Positive Selection. Mol. Cell. Biol. 22: 4556-4566 [Abstract] [Full Text]  
• Berki, T., Palinkas, L., Boldizsar, F., Nemeth, P. (2002). Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations. Int Immunol 14: 463-469 [Abstract] [Full Text]  
• Murray, S. E., Lallman, H. R., Heard, A. D., Rittenberg, M. B., Stenzel-Poore, M. P. (2001). A Genetic Model of Stress Displays Decreased Lymphocytes and Impaired Antibody Responses Without Altered Susceptibility to Streptococcus pneumoniae. J. Immunol. 167: 691-698 [Abstract] [Full Text]  
• Han, S., Choi, H., Ko, M.-g., Choi, Y. I., Sohn, D. H., Kim, J. K., Shin, D., Chung, H., Lee, H. W., Kim, J.-B., Park, S. D., Seong, R. H. (2001). Peripheral T Cells Become Sensitive to Glucocorticoid- and Stress-Induced Apoptosis in Transgenic Mice Overexpressing SRG3. J. Immunol. 167: 805-810 [Abstract] [Full Text]  
• Lechner, O., Dietrich, H., Wiegers, G. J., Vacchio, M., Wick, G. (2001). Glucocorticoid production in the chicken bursa and thymus. Int Immunol 13: 769-776 [Abstract] [Full Text]  
• Conte, D., Liston, P., Wong, J. W., Wright, K. E., Korneluk, R. G. (2001). Thymocyte-targeted overexpression of xiap transgene disrupts T lymphoid apoptosis and maturation. Proc. Natl. Acad. Sci. USA 10.1073/pnas.081547998v1 [Abstract] [Full Text]  
• Van Laethem, F., Baus, E., Smyth, L. A., Andris, F., Bex, F., Urbain, J., Kioussis, D., Leo, O. (2001). Glucocorticoids Attenuate T Cell Receptor Signaling. JEM 193: 803-814 [Abstract] [Full Text]  
• Savino, W., Dardenne, M. (2000). Neuroendocrine Control of Thymus Physiology. Endocr. Rev. 21: 412-443 [Abstract] [Full Text]  
• Wiegers, G. J., Stec, I. E. M., Klinkert, W. E. F., Reul, J. M. H. M. (2000). Glucocorticoids Regulate TCR-Induced Elevation of CD4: Functional Implications. J. Immunol. 164: 6213-6220 [Abstract] [Full Text]  
• Sayegh, C. E., Ratcliffe, M. J. H. (2000). Perinatal Deletion of B Cells Expressing Surface Ig Molecules That Lack V(D)J-Encoded Determinants in the Bursa of Fabricius Is Not Due to Intrafollicular Competition. J. Immunol. 164: 5041-5048 [Abstract] [Full Text]  
• Jenkinson, E. J., Parnell, S., Shuttleworth, J., Owen, J. J. T., Anderson, G. (1999). Specialized Ability of Thymic Epithelial Cells to Mediate Positive Selection Does Not Require Expression of the Steroidogenic Enzyme P450scc. J. Immunol. 163: 5781-5785 [Abstract] [Full Text]  
• Sacedon, R., Vicente, A., Varas, A., Jimenez, E., Munoz, J. J., Zapata, A. G. (1999). Glucocorticoid-mediated regulation of thymic dendritic cell function. Int Immunol 11: 1217-1224 [Abstract] [Full Text]  
• Vacchio, M. S., Lee, J. Y. M., Ashwell, J. D. (1999). Thymus-Derived Glucocorticoids Set the Thresholds for Thymocyte Selection by Inhibiting TCR-Mediated Thymocyte Activation. J. Immunol. 163: 1327-1333 [Abstract] [Full Text]  
• PAZIRANDEH, A., XUE, Y., RAFTER, I., SJÖVALL, J., JONDAL, M., OKRET, S. (1999). Paracrine glucocorticoid activity produced by mouse thymic epithelial cells. FASEB J. 13: 893-901 [Abstract] [Full Text]  
• Wang, W., Wykrzykowska, J., Johnson, T., Sen, R., Sen, J. (1999). A NF-{kappa}B/c-myc-Dependent Survival Pathway Is Targeted by Corticosteroids in Immature Thymocytes. J. Immunol. 162: 314-322 [Abstract] [Full Text]  
• Jiang, S.-P., Vacchio, M. S. (1998). Cutting Edge: Multiple Mechanisms of Peripheral T Cell Tolerance to the Fetal ""Allograft"". J. Immunol. 160: 3086-3090 [Abstract] [Full Text]  
• Conte, D., Liston, P., Wong, J. W., Wright, K. E., Korneluk, R. G. (2001). Thymocyte-targeted overexpression of xiap transgene disrupts T lymphoid apoptosis and maturation. Proc. Natl. Acad. Sci. USA 98: 5049-5054 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS