Control of T-cell activation by CD4+ CD25+ suppressor T cells

Depletion of the minor (similar to 10%) subpopulation of CD4(+) T cells that co-expresses CD25 (interleukin (IL)-2 receptor alpha -chain) by thymectomy of neonates on the third day of life or by treatment of adult CD4(+) T cells with anti-CD25 a-nd complement results in the development of organ-specific autoimmunity, Autoimmune disease can be prevented by reconstitution of the animals with CD4(+) CD25 (+) cells. CD4(+) CD25(+)mediated protection of autoimmune gastritis does not require die suppressor cytokines IL-4, IL-10, or transforming growth factor (TGF)-beta. Mice that express a transgenic T-cell receptor (TCR) derived from a thymectomized newborn that recognizes the gastric parietal cell antigen H/ K ATPase all develop severe autoimmune gastritis very early in life. CD4(+) CD25(+) T cells are also powerful suppressors of the activation of both CD4(+) and CD8(+) T cells in vitro. Suppression is mediated by a cell contactdependent, cytokine-independent T-T interaction. Activation of CD4(+) CD25(+) via their TCR generates suppressor effector cells that are capable of non-specifically suppressing the activation of any CD4(+) or CDS+ T cell. Activation of suppressor effector function is independent of co-stimulation mediated by CD28/CTLA-4 interactions with CD80/CD86. We propose that CD4(+) CD25(+) T cells recognize organ-specific antigens, are recruited to sites of autoimmune damage where they are activated by their target antigen, and then physically interact with autoreactive CD4(+) or CD8(+) effector cells to suppress the development of autoimmune disease.