CD4(-CELLS INHIBIT BOTH THE INDUCTION AND EFFECTOR FUNCTION OF AUTOREACTIVE T-CELLS AND REPRESENT A UNIQUE LINEAGE OF IMMUNOREGULATORY CELLS()CD25(+) T)

Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by rec onstitution of the thymectomized animals early in life with normal adu lt lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4(+) T cells, It has been d emonstrated recently that the regulatory CD4(+) T cells that prevent d isease coexpress CD25. We have further characterized the population of CD4(+)CD25(+) immunoregulator cells and demonstrated that they can su ppress not only the induction of disease post-thymectomy but can also efficiently suppress disease induced by cloned autoantigen-specific ef fecter cells. Furthermore, the CD4(+)CD25(+) T cells appear to be memb ers of a unique lineage of regulatory T cells, as the induction of CD2 5 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly su sceptible to autoimmune disease induced by the cloned line of autoanti gen-specific effecters, while normal mice were relatively resistant. T he capacity; of the cloned line to transfer disease to nulnu recipient s could be inhibited by normal spleen cell populations containing CD4( +)CD25(+) cells and by purified CD4(+)CD25(+) cells. Although the targ et Ag(s) and mechanism of action of the CD4(+)CD25(+) T cells remain t o be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of ''ignorant'' self-reactive T cells present in the normal peripheral lymphocyte pool.