Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state

Elimination of CD25+ T cells, which constitute 5-10% of peripheral CD4+ Tcells in normal naive mice, leads to spontaneous development of variousautoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturallyunresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation,suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigenconcentration required for stimulating CD25+CD4+ T cells to exertsuppression is much lower than that required for stimulating CD25-CD4+ Tcells to proliferate. The suppression, which results in reduced IL-2production by CD25-CD4+ T cells, is dependent on cellular interactions onantigen-presenting cells (and not mediated by far-reaching or long-lastinghumoral factors or apoptosis-inducing signals) and antigen non-specific inits effector phase. Addition of high doses of IL-2 or anti-CD28 antibody tothe in vitro T cell stimulation culture not only breaks the anergic stateof CD25+CD4+ T cells, but also abrogates their suppressive activitysimultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ Tcells appeared to be their basal default condition, since removal of IL-2or anti-CD28 antibody from the culture milieu allows them to revert to theoriginal anergic/suppressive state. Furthermore, transfer of suchanergy/suppression-broken T cells from normal mice produces variousautoimmune diseases in syngeneic athymic nude mice. These results takentogether indicate that one aspect of immunologic self-tolerance ismaintained by this unique CD25+CD4+ naturally anergic/suppressive T cellpopulation and its functional abnormality directly leads to the developmentof autoimmune disease.