Immunologic Self-Tolerance Maintained by Activated T Cells Expressing 11-2 Receptor a-Chains (CD25) Breakdown of a Single Mechanism of Self-Tolerance Causes Various

Approximately 10 % of peripheral CD4+ cells and less than 1 YO of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor a-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, al l recipients spontaneously developed histologically and serologically evi-dent autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulo-nephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune de-velopments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, pre-sumably at the T cell activation stage; elirnination/reduction of CD4+CD25+ cells relieves this general suppres-sion, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses t