The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/6/2033/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 11, June 2, 1997 2033-2038

Brief Definitive Reports

Thymus-derived Glucocorticoids Regulate Antigen-specific Positive Selection

Melanie S. Vacchio* and Jonathan D. Ashwell{ddagger}

From the * Laboratory of Immunology, Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20852; and {ddagger} 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 {alpha}/β-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.

Address correspondence to Melanie S. Vacchio, Food and Drug Administration, Center for Biologics Evaluation and Review, Suite 200N/HFM 538, 1401 Rockville Pike, Rockville, MD 20852-1448.


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