Resistance of single-positive thymocytes to glucocorticoid-induced apoptosis is mediated by CD28 signaling

J van den Brandt, D Wang… - Molecular …, 2004 - academic.oup.com
J van den Brandt, D Wang, HM Reichardt
Molecular Endocrinology, 2004academic.oup.com
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 …
Abstract
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-XL 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.
Oxford University Press