The influence of glucocorticoids and a downstream target on the development of T cells

Abstract

Evidence suggests that glucocorticoids producei:l by thymic epithelial cells modify the biological consequences of TCR-mediated signaling. We hypothesized that glucocorticoids modulate the threshold for thymocyte activation by opposing the consequences of TCR engagement. To examine this possibility, TKO mice, which have a 50% reduction in thymocyte glucocorticoid receptor expression, were bred with mouse strains differing in their ability to present peptides in the context of MHC-encoded molecules. Our results indicate that endogenous glucocorticoids affect thymic selection by decreasing a thymocyte's sensitivity to TCR engagement. Thymocytes with increased avidities for self-peptide/MHC complexes are thought to adopt a regulatory (CD4+CD25) T cell lineage. We_ hypothesized that altering how a thymocyte perceives TCR engagement by modulating glucocorticoid responsiveness will influence a CD4+ T cell's choice to commit to a CD4+CD25+ regulatory T cell lineage. In mice, abundantly expressing a few or one peptide(s) bound to MHC class II molecules, a disproportionate number CD4+ T cells were committed to a regulatory (CD4+CD25+) lineage when the threshold required for thymocyte activation was reduced. Thus, increasing the perceived intensity of TCR engagement during thymic selection enhanced commitment to a CD4+CD25+ regulatory lineage. A reduction in GR signaling by early thymic precursors was found to result in a selective defect in uP but not yo lineage development. Few DN precursors from TKO 'mice were found to express intrac.ellular TCR P-chains, while the expression of other components of the pre-TCR was not affected. A more detailed analysis of the TCR P locus revealed that glucocorticoid hyporesponsiveness inhibited the rearrangement of this gene. It has been demonstrated that GITR (Glucocorticoid Induced TNF-like Receptor), a non-death domain containing TNF family member whose expression is induced by glucocorticoids, . prevents TCR-induced apoptosis when over-expressed in T cell hybridomas. We hypothesized that GITR plays an important role in thymocyte development by enhancing the survival/selection of immature thymocytes. To investigate this possibility in vivo, we produced transgenic mice that over-expressed GITR specifically on thymocytes. Ectopic GITR expression did not prevent TCR-induced thymocyte apoptosis in vivo implying that GITR expression does not enhance selection, but is rather a consequence of it.