CD4(-CELLS SUPPRESS POLYCLONAL T-CELL ACTIVATION IN-VITRO BY INHIBITING INTERLEUKIN-2 PRODUCTION()CD25(+) IMMUNOREGULATORY T)

Peripheral tolerance may be maintained by a population of regulatory/s uppressor T cells that prevent the activation of autoreactive T cells recognizing tissue-specific antigens. We have previously shown that CD 4(+)CD25(+) T cells represent a unique population of suppressor T cell s that can prevent both the initiation of organ-specific autoimmune di sease after day 3 thymectomy and the effector function of cloned autoa ntigen-specific CD4(+) T cells. To analyze the mechanism of action of these cells, we established an in vitro model system that mimics the f unction of these cells in vivo. Purified CD4(+)CD25(+) cells failed to proliferate after stimulation with interleukin (IL)-2 alone or stimul ation through the T cell receptor (TCR). When cocultured With CD4(+)CD 25(-) cells, the CD4(+)CD25(+) cells markedly suppressed proliferation by specifically inhibiting the production of TL-2. The inhibition was not cytokine mediated, was dependent on cell contact between the regu latory cells and the responders, and required activation of the suppre ssors via the TCR. Inhibition could be overcome by the addition to the cultures of IL-2 or anti-CD28, suggesting that the CD4(+)CD25(+) cell s may function by blocking the delivery of a costimulatory signal. Ind uction of CD25 expression on CD25(-) T cells in vitro or in vivo did n ot result in the generation of suppressor activity. Collectively, thes e data support the concept that the CD4(+)CD25(+) T cells in normal mi ce may represent a distinct lineage of ''professional'' suppressor cel ls.