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Resistance of Single-Positive Thymocytes to Glucocorticoid-Induced Apoptosis Is Mediated by CD28 Signaling

Institute of Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany

Address all correspondence and requests for reprints to: Holger M. Reichardt, Institute of Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany. E-mail: holger.reichardt{at}mail.uni- wuerzburg.de.

Glucocorticoids administered in pharmacological doses potently induce apoptosis in immature double-positive thymocytes. In contrast, single-positive thymocytes are completely resistant. We now provide evidence that this difference can be attributed to CD28 signaling. When taken into culture, single-positive thymocytes also become sensitive to glucocorticoid-induced apoptosis, which can be prevented by enforced CD28 engagement using a novel type of antibody. This is achieved, at least in part, by transcriptional regulation of apoptosis-related genes such as Bcl-X_L via a calcium- and phosphatidylinositol 3 kinase-dependent pathway. Accordingly, deficiency of CD28 in genetically engineered mice leads to an increased sensitivity of single-positive thymocytes toward glucocorticoid-induced cell death in vivo. Taken together, we have identified CD28 signaling in the thymus as a key player in determining the differential sensitivity of double-positive and single-positive cells to glucocorticoid action.

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