Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation

To elucidate the role of CD4(+)CD25(+) regulatory T cells in oral tolerance, we used the model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene(DNFB), which is mediated by CD8(+) Tc1 effector cells independently of CD4(+) T-cell help. Conversely to normal mice, invariant chain knock-out (KO) (li(%)) mice, which are deficient in CD4(+) T cells, cannot be orally tolerized and develop a chronic hapten-specific CHS response. Transfer of naive CD4(+) T cells before hapten gavage into li(%) mice restores oral tolerance by a mechanism independent of interleukin-10 (IL-10) production by CD4(+) T cells. That naturally occurring CD4(+)CD25(+) T cells are critical for oral tolerance induction is demonstrated by the finding that (1) transfer of CD4+CD25+ but not CD4(+)CD25(-) T cells into li(%) recipients completely prevents the CHS response and skin infiltration by CD8(+) T cells, by blocking development of hapten-specific CD8(+) T cells; (2) in vivo depletion of CD4(+)CD25(+) cells by antibody treatment in normal mice impairs oral tolerance; and (3) CD4(+)CD25(+) T cells inhibit hapten-specific CD8(+) T-cell proliferation and interferon gamma (IFNgamma) production, in vitro. These data show that naturally occurring CD4(+)CD25(+) T cells are instrumental for orally induced tolerance and are key actors for the control of antigen-specific CD8(+) T-cell effectors mediating skin inflammation. (C) 2003 by The American Society of Hematology.