The first evidence for a role of CD4+CD25+ Tregs was provided by studies in murine models of atherosclerosis, showing that Treg depletion obtained either by gene deletion (CD80/86, CD28, inducible T-cell costimulator (ICOS)) or following treatment with CD25-neutralizing antibodies exacerbated atherosclerosis [7,55]. The gene discussed is ICOS; the disease is atherosclerosis.