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

Abstract

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.

Certified Professionals

“…This may be secondary to the purity of the CD25 + cells used in the assay and the specific assay (protein or mRNA). As has been reported with murine CD25 + T cells 4 6, human CD25 + T cells appear to be capable of producing low levels of IL-10 and perhaps TGF-β, although equivalent levels of TGF-β mRNA were also detectable in stimulated CD25 − T cells 16. Suppression in cocultures of CD25 + /CD25 − T cells could be abrogated to some extent by the addition of IL-2, IL-4, or IL-15, alone or in combination.…”

“…Rapid progress in the analysis of the regulatory function of the CD4 + CD25 + T cell population was made by the development of in vitro model systems that mimicked the function of these cells in vivo 4 5 6. Although minor differences were observed in the results obtained by the different groups, it is widely accepted that these cells are both hyporesponsive and suppressive.…”

CD25+ Treg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

“…Our findings are compatible with these previous findings by others, because also in ROH high mice some autoreactive CD4 T cell help was present. By controlling autoreactive Th cells, T reg are suitable to complement well-characterized anergy induction for maintaining B-cell tolerance.FoxP3 + T reg are thought to arise in the thymus, while the questions regarding their induction in secondary lymphatics and their antigen-specificity remain controversial [22,23,[33][34][35][36][37][38]. A distinct T reg subset expressing T-cell activation markers underwent cell cycles in LN draining sites of antigen expression [26], implying antigen-specificity.…”

Non‐Th2 Regulatory T‐Cell Control of Th1 Autoimmunity

“…In particular, the effect of these cells on antigen or anti-TCR antibody-induced T-cell proliferation was examined. Although the significance of these models remains to be proven, evidence has been collected to indicate the importance of cell± cell contact (the effect is lost when the interacting cells are separated by a cell impermeable membrane) [73]. CD25 T cells could act by interacting with APCs in various ways.…”