CD4+CD25+ and CD1d-restricted natural killer T (NKT) cells are thymus-derived self-reactive regulatory T cells that play a key role in the control of pathological immune responses. Little is known about functional cooperation between innate regulatory NKT cells and adaptive CD4+CD25+ regulatory cells. Here we show that human CD4+Vα24+Vβ11+ (CD4+ NKT) cells isolated from peripheral blood by flow cytometric cell sorting secrete substantial amounts of IL-2 after stimulation with dendritic cells (DC) and α-Galactosylceramide. When cocultured with CD4+CD25+ cells, CD4+ NKT cells promoted moderate proliferation of CD4+CD25+ cells. The proliferation of CD4+CD25+ T cells was due to soluble IL-2 produced by activated CD4+ NKT cells. The expanded CD4+CD25+ cells remained anergic and retained their potent suppressive properties. These findings indicate that unlike conventional CD4+ and CD8+ T cells, which are susceptible to CD4+CD25+ regulatory cell suppression, NKT cells promote CD4+CD25+ regulatory cell proliferation. These data raise the possibility that NKT cells can function as helper cells to CD4+CD25+ regulatory T cells, thereby providing a link between the two naturally occurring populations of regulatory T cells.