Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells:: induction of autoimmune disease by breaking their anergic/suppressive state
Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells:: induction of autoimmune disease by breaking their anergic/suppressive state
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DOI：
10.1093/intimm/10.12.1969
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发表时间：
1998-12-01
影响因子：
4.4
通讯作者：
Sakaguchi, S
中科院分区：
文献类型：
--
作者：
Takahashi, T;Kuniyasu, Y;Sakaguchi, S
CD 25（+）T细胞（其构成正常幼稚小鼠中外周CD 4（+）T细胞的5-10%）的消除导致各种自身免疫性疾病的自发发展。这些免疫调节性CD 25（+）CD 4（+）T细胞在体外对TCR刺激天然无应答（无反应性），并且在刺激时抑制CD 25（-）CD 4（+）T细胞和CD 8（+）T细胞的增殖。刺激CD 25（+）CD 4（+）T细胞发挥抑制作用所需的抗原浓度远低于刺激CD 25-CD 4 + T细胞增殖所需的抗原浓度。这种抑制导致CD 25（-）CD 4（+）T细胞产生IL-2减少，依赖于抗原呈递细胞上的细胞相互作用（而不是由深远或持久的体液因子或免疫诱导信号介导）和效应期的抗原非特异性。向体外T细胞刺激培养物中加入高剂量的IL-2或抗CD 28抗体不仅打破了CD 25（+）CD 4（+）T细胞的无反应性状态，而且同时消除了它们的抑制活性。重要的是，CD 25（+）CD 4（+）T细胞的无反应性/抑制状态似乎是它们的基础默认状态，因为从培养环境中去除IL-2或抗CD 28抗体允许它们恢复到原始的无反应性/抑制状态。此外，从正常小鼠转移这种无反应性/抑制破坏的T细胞在同基因无胸腺裸鼠中产生各种自身免疫性疾病。这些结果共同表明，免疫自身耐受的一个方面是由这种独特的CD 25（+）CD 4（+）天然无反应性/抑制性T细胞群维持的，其功能异常直接导致自身免疫性疾病的发展。
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.