Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells

Nonactivated CD4 + CD25 + regulatory T cells constitutively express glucocorticoid-induced TNFR family-related receptor (GITR), a TNFR family member whose engagement was presumed to abrogate regulatory T cell-mediated suppression. Using GITR −/− mice, we report that GITR engagement on CD25 − , not CD25 + T cells abrogates T cell-mediated suppression. Mouse APCs constitutively express GITR ligand (GITR-L), which is down-regulated following TLR signaling in vivo. Although GITR −/− CD25 − T cells were capable of mounting proliferative responses, they were incapable of proliferation in the presence of physiological numbers of CD25 + T cells. Thus, GITR-L provides an important signal for CD25 − T cells, rendering them resistant to CD25 + -mediated regulation at the initiation of the immune response. The down-regulation of GITR-L by inflammatory stimuli may enhance the susceptibility of effector T cells to suppressor activity during the course of an infectious insult.