Decreasing the threshold for thymocyte activation biases CD4+ T cells toward a regulatory (CD4+CD25+) lineage

Thymus-derived CD4(+)CD25(+) regulatory T (T) cells play a critical role in suppressing aberrant responses to self in vivo. The factors that influence a CD4(+) T cell's decision to commit to an immunoregulatory T-r cell lineage are currently unknown. In the present study, we found that in mice, abundantly expressing a few or one peptide(s) bound to MHC class II molecules, a large portion of conventional CD4(+) T cells could be biased towards the commitment to a T-r lineage by reducing the threshold required for thymocyte activation. This occurred in the presence of either an antisense glucocorticoid receptor transgene or a pharmacological inhibitor of glucocorticoid synthesis. These results demonstrate a novel in vivo pathway for the generation of T-r cells, and raise the possibility that therapeutic enhancement of the T-r cell repertoire through pharmacological manipulation of TCR signaling thresholds may provide a feasible means of ameliorating autoimmunity.