Thymocyte apoptosis induced by T cell activation is mediated by glucocorticoids in vivo.
Glucocorticoids, administered in pharmacological doses, potently modulate immune system function and are a mainstay therapy for many common human diseases. Physiologic production of glucocorticoids may play a role in optimization of the immune repertoire both centrally and peripherally. Possible effects include alteration of lymphocyte development and down-regulation of cytokine responses, but essential roles remain unclear. To determine the part that endogenous glucocorticoids play in thymocyte development, we used fetal liver from mice lacking the glucocorticoid receptor GRko for immunological reconstitution of lethally irradiated wild-type (WT) mice. We find normal numbers and subset distribution of GRko thymocytes. GRko thymocytes also exhibit similar sensitivity to apoptosis induced by activating anti-CD3epsilon Ab as WT thymocytes in vitro. Surprisingly, GRko thymocytes are significantly more resistant than WT thymocytes to anti-CD3epsilon-mediated thymocyte apoptosis in vivo. Consistent with this finding, in vivo TCR complex activation induces sustained high levels of glucocorticoids that correlate strongly with thymocyte apoptosis in WT mice. We find that while direct engagement of the TCR complex may cause death of a subset of thymocytes, glucocorticoids are required for deletion of the majority of thymocytes. Thus, TCR stimulation by Ab administration may more accurately reflect polyclonal T cell activation than negative selection in vivo.
Brewer
Judson A
JA
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kanagawa
Osami
O
Sleckman
Barry P
BP
Muglia
Louis J
LJ
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D017252:CD3 Complex; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000002:abnormalities; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D017252:CD3 Complex; C115335:CD3E protein, human; D005938:Glucocorticoids; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D003345:Corticosterone