The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo
The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo
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DOI：
10.1172/jci35834
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发表时间：
2008-11-01
影响因子：
15.9
通讯作者：
Akbar, Arne N.
中科院分区：
文献类型：
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作者：
Vukmanovic-Stejic, Milica;Agius, Elaine;Akbar, Arne N.
天然存在的 CD4(+)CD25(hi)Foxp3(+) Tregs (nTreg) 在血液中高度增殖。然而，它们在局部抗原特异性 T 细胞反应过程中积累和增殖的动力学目前尚不清楚。为了探索这一点，我们使用了人体实验系统，将结核菌素纯化蛋白衍生物 (PPD) 注射到皮肤中，并分析随时间推移的局部 T 细胞反应。 CD4(+)Foxp3(-)（记忆）和CD4(+)Foxp3(+)（推定nTreg）T细胞的数量平行增加，两个群体以相同的相对速率增殖。与CD4+Foxp3-T细胞群相比，皮肤CD4+Foxp3+T细胞表达典型的Treg标记（即CD25(hi)、CD127(lo)、CD27(+)和CD39(+)），并且在体外再刺激后不合成IL-2或IFN-γ，表明它们不是最近激活的效应细胞。为了确定皮肤中的CD4(+)Foxp3(+) T细胞是否可以由记忆CD4(+) T细胞诱导产生，我们在体外扩增了皮肤来源的记忆CD4+ T细胞并对其进行了激活。这些细胞表达高水平的 CD25 和 Foxp3，并抑制皮肤源性应答 T 细胞对 PPD 攻击的增殖。因此，我们的数据表明，记忆和 CD4(+) Treg 群体在二次抗原反应期间受到串联调节。此外，还可以从发炎组织中分离出效应 CD4+ T 细胞群，并操纵它们生成具有抑制炎症反应潜力的 Tregs。
Naturally occurring CD4(+)CD25(hi)Foxp3(+) Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4(+)Foxp3(-) (memory) and CD4(+)Foxp3(+) (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4+Foxp3- T cell populations, skin CD4+Foxp3+ T cells expressed typical Treg markers (i.e., they were CD25(hi), CD127(lo), CD27(+), and CD39(+)) and did not synthesize IL-2 or IFN-gamma after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4(+)Foxp3(+) T cells in skin could be induced from memory CD4(+) T cells, we expanded skin-derived memory CD4+ T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4(+) Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4+ T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses.