Glucocorticoid resistance in thymocytes from mice expressing a T cell receptor transgene

A majority of thymocytes undergo apoptosis during differentiation due to la ck of survival signals provided by T cell receptor (TCR) activation. As glu cocorticoids (GC) have been suggested to be involved in this process, we ha ve investigated the GC sensitivity in thymocytes from mice expressing a tra nsgenic selecting TCR, We now report that immature CD4(+)CD8(+) double-posi tive thymocytes from these mice are comparatively more resistant to cortico sterone-induced apoptosis, This is associated with reduced glucocorticoid r eceptor (GR) expression, increased levels of membrane CD28, increased NF-ka ppa B DNA binding activity, and increased binding to the CD28 response elem ent in the interleukin-a gene promoter. Analysis of NF kappa B/Rel proteins from nuclear extracts demonstrated altered levels of some of these protein s. Our results suggest that TCR recognition of self major histocompatibilit y antigens generates intracellular signals which alter the thymocyte GC sen sitivity and thereby protect them against apoptosis induced by endogenous G C. (C) 2000 Academic Press.