International Immunology, Vol 10, 1969-1980, Copyright © 1998 by Oxford University Press
T Takahashi, Y Kuniyasu, M Toda, N Sakaguchi, M Itoh, M Iwata, J Shimizu and S Sakaguchi
Elimination of CD25+ T cells, which constitute 5-10% of peripheral CD4+ T
cells in normal naive mice, leads to spontaneous development of various
autoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturally
unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation,
suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigen
concentration required for stimulating CD25+CD4+ T cells to exert
suppression is much lower than that required for stimulating CD25-CD4+ T
cells to proliferate. The suppression, which results in reduced IL-2
production by CD25-CD4+ T cells, is dependent on cellular interactions on
antigen-presenting cells (and not mediated by far-reaching or long-lasting
humoral factors or apoptosis-inducing signals) and antigen non-specific in
its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to
the in vitro T cell stimulation culture not only breaks the anergic state
of CD25+CD4+ T cells, but also abrogates their suppressive activity
simultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ T
cells appeared to be their basal default condition, since removal of IL-2
or anti-CD28 antibody from the culture milieu allows them to revert to the
original anergic/suppressive state. Furthermore, transfer of such
anergy/suppression-broken T cells from normal mice produces various
autoimmune diseases in syngeneic athymic nude mice. These results taken
together indicate that one aspect of immunologic self-tolerance is
maintained by this unique CD25+CD4+ naturally anergic/suppressive T cell
population and its functional abnormality directly leads to the development
of autoimmune disease.
ARTICLES
Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state
Department of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Japan.
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