Regulatory T cell proliferative potential is impaired in human autoimmune disease
Regulatory T cell proliferative potential is impaired in human autoimmune disease
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DOI：
10.1038/nm.3411
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发表时间：
2014-01-01
期刊：
影响因子：
82.9
通讯作者：
Matarese, Giuseppe
中科院分区：
文献类型：
--
作者：
Carbone, Fortunata;De Rosa, Veronica;Matarese, Giuseppe
人 CD4(+)CD25(high)CD127(-)FoxP3(+) 调节性 T (Treg) 细胞可抑制体外和体内的免疫反应 (1)。先前已报道过自身免疫性疾病中外周 T-reg 细胞的抑制功能和/或数量减少(2,3)。 T-reg 细胞是体内 CD4(+) 细胞内复制最活跃的区室，但它们在体外对经典 T 细胞受体 (TCR) 刺激反应迟缓，这是继发于其过度活跃代谢状态的情况 (4,5)。在这里，我们报告说，由于白细胞介素 2 (IL-2) 分泌和 IL-2 受体 (IL-2R) 信号转导器和转录激活剂 5 (STAT5) 信号传导的改变，复发缓解型多发性硬化症 (RRMS) 受试者中 TCR 刺激后 T-reg 细胞的增殖受到损害。这与叉头盒 P3 (FoxP3) 44-和 47-kDa 剪接形式的表达减少、S6 核糖体蛋白（雷帕霉素靶标哺乳动物 mTOR 的下游靶标）过度激活以及细胞周期蛋白依赖性激酶抑制剂 p27 (p27(kip1)) 和细胞外信号相关激酶 1 和 2 (ERK1/2) 的活性改变有关。 RRMS中T-reg细胞增殖能力受损与受试者的临床状态相关，其中疾病严重程度的增加与T-reg细胞增殖的下降相关。这些结果表明一种以前未被认识的机制可能解释了自身免疫性疾病中 T-reg 细胞的逐渐丧失。
Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo(1). Reduced suppressive function and/or number of peripheral T-reg cells has been previously reported in autoimmune disorders(2,3). T-reg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state(4,5). Here we report that proliferation of T-reg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of T-reg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in T-reg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of T-reg cells in autoimmune disease.