A peripheral circulating compartment of natural naive CD4+ Tregs
A peripheral circulating compartment of natural naive CD4+ Tregs
复制标题
DOI：
10.1172/jci23963
复制
发表时间：
2005-07-01
影响因子：
15.9
通讯作者：
Ayyoub, M
中科院分区：
文献类型：
--
作者：
Valmori, D;Merlo, A;Ayyoub, M
CD4(+)CD25(+) treg通过控制自身反应性T细胞在维持外周自身耐受性中发挥核心作用。尽管CD4(+)CD25(+) Tregs作为一个独特的谱系，其胸腺起源已经被推断出来，但对其发育途径的理解仍然难以捉摸。在小鼠和人类中，外周CD4(+)CD25(+) Treg群被描述为由抗原经历的T细胞组成，这些T细胞在TCR刺激后不能显著增殖，但会抑制CD25-T细胞的增殖和效应功能。在这里，我们展示了CD25在人循环CD4(+) T淋巴细胞体内分化阶段的表达分析，确定了CD45RA(+)/RO-幼稚部分中包含的CD25(+)CCR7(+)CD62L(+)CTLA-4(+)FOXP3（+）细胞的一个独特子集。我们将该子集命名为自然幼稚Tregs (NnTregs)，它在年轻人中表现突出，并随着年龄的增长而减少。在缺乏IL-2的情况下，NnTregs在刺激后无能，并发挥体外细胞-细胞接触介导的抑制功能。此外，它们在自体apc的刺激下增殖，这表明在携带自反应性tcr的T细胞中高度富集。这一亚群的定义对于分析人类自然发生的treg及其在治疗性免疫干预中的靶向具有重要意义。
CD4(+)CD25(+) Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4(+)CD25(+) Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4(+)CD25(+) Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25-T cells. Here we show that analysis of CD25 expression in human circulating CD4(+) T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25(+)CCR7(+)CD62L(+)CTLA-4(+)FOXP3(+) cells contained in the CD45RA(+)/RO- naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4(+) population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact-mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.