Resistance of single-positive thymocytes to glucocorticoid-induced apoptosis is mediated by CD28 signaling.
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.
van den Brandt
Jens
J
Institute of Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany.
Wang
Dapeng
D
Reichardt
Holger M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018106:CD28 Antigens / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015704:CD4 Antigens / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
D018106:CD28 Antigens; D015704:CD4 Antigens; D002118:Calcium; D002147:Calmodulin; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C494773:Bak1 protein, mouse; C494774:Bak1 protein, rat; C494812:Bcl2l1 protein, mouse; C494813:Bcl2l1 protein, rat