Thymocyte resistance to glucocorticoids leads to antigen-specific unresponsiveness due to "holes" in the T cell repertoire

We have proposed that glucocorticoids antagonize TCR-mediated activation an d influence which TCR avidities result in positive or negative selection. W e now analyze the immune response of mice whose thymocytes express antisens e transcripts to the glucocorticoid receptor (TKO mice). TKO mice responded normal ly to the complex antigen PPD but were proliferative nonresponders to pigeon cytochrome c 81-104 (PCC), having a large decrease in the frequen cy of PCC-responsive CD4(+) T cells. Unlike wild-type T cells, few TKO T ce lls in PCC-specific cell lines expressed V alpha 11(+)V beta 3(+). Furtherm ore, for naive CD4(+) T cells from unimmunized TKO mice, the frequencies of many of the molecular features common to the CDR3 regions of PCC-responsiv e V alpha 11(+)V beta 3(+) cells were substantially decreased. Thus, thymoc yte glucocorticoid hyporesponsiveness resulted in loss of cells capable of responding to PCC, corresponding to an antigen-specific "hole" in the T cel l repertoire.