Mechanisms responsible for peripheral immune tolerance are currently under investigation in several laboratories, in order to define the role of immune homeostasis in physiological processes and pathologic conditions, such as autoimmunity and cancer. In this context, recent studies attributed a relevant role to the glucocorticoid-induced TNFR-related gene (GITR). GITR is expressed at high levels on CD4(+)CD25(+). T regulatory (Treg) cells, but only at low levels on resting responder T lymphocytes, and is upregulated after activation. GITR triggering induces both pro- and anti-apoptotic effects through different intracellular pathways, abrogates the suppressive activity of Treg cells, and co-stimulates responder T cells. These data hint that GITR triggering overstimulates the immune system. Indeed, in vivo studies demonstrated that GITR stimulation may both induce autoimmune diseases and strengthen anti-virus and anti-tumor immune responses. Therefore, the GITR-GITRL system appears crucial in regulating immunity. Currently, the majority of studies about GITR's role on regulatory cells are focused on CD4(+)CD25(+) Treg cells, while very little is known about the importance of this molecule in other Treg subtypes. We have recently characterized a subpopulation of CD8+ T suppressor lymphocytes able to inhibit both T cell proliferation and cytotoxicity. Preliminary data show that GITR is expressed on such CD8+ T suppressor cells and that its activation by a specific antibody inhibits generation, but not function, of these cells. These early results suggest the importance of GITR in human T suppressor lymphocytes other than CD4(+)CD25(+) Treg cells.