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Departments of
* Pediatrics, Molecular Biology, and Pharmacology, and
Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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-CD3
Ab as WT thymocytes in vitro. Surprisingly,
GRko thymocytes are significantly more resistant than WT thymocytes to
anti-CD3-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.
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