Activated CD1d‐restricted natural killer T cells secrete IL‐2: innate help for CD4+CD25+ regulatory T cells?

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(+)Valpha24(+)Vbeta11(+) (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 alpha-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.