Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+ CD25+ regulatory T cells
Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+ CD25+ regulatory T cells
复制标题
DOI：
10.1038/nm1312
复制
发表时间：
2005-11-01
期刊：
影响因子：
82.9
通讯作者：
Mackall, CL
中科院分区：
文献类型：
--
作者：
Zhang, H;Chua, KS;Mackall, CL
CD 4（+）CD 25（+）调节性T（T-reg）细胞在维持免疫耐受中具有关键作用。出生时缺乏Treg细胞的小鼠和人类发展为严重的自身免疫性疾病（1，2），淋巴细胞减少小鼠中Treg细胞的耗竭诱导自身免疫（3，4）。白细胞介素（IL）-2信号传导是胸腺发育（5）、外周扩增（6）和T（reg）细胞抑制活性（7）所必需的。缺乏IL-2的动物死于自身免疫（8，9），这可通过给予IL-2应答性T（reg）细胞来预防（5）。鉴于IL-2的主要生理作用之一是产生和维持T-reg细胞（10）的新证据，出现了IL-2治疗对其影响的问题。我们在接受或未接受IL-2治疗的癌症患者的免疫重建过程中监测了Treg细胞。在免疫重建过程中，CD 4（+）CD 25（hi）细胞经历了稳态外周扩增，在接受IL-2的淋巴细胞减少个体中，T-reg细胞区室显著增加。小鼠研究表明，IL-2治疗诱导正常宿主中存在的T-reg细胞的扩增，并且IL-2诱导的T-reg细胞扩增通过淋巴细胞减少进一步增强。在每个细胞的基础上，与正常宿主中存在的Treg细胞相比，IL-2治疗产生的T-reg细胞表达相似水平的FOXP 3，并且具有相似的抑制效力。这些研究表明，IL-2和淋巴细胞减少症是CD 4（+）CD 25（+）T-reg细胞稳态的主要调节剂。
CD4(+)CD25(+) regulatory T ( T-reg) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking Treg cells develop severe autoimmune disease(1,2), and depletion of Treg cells in lymphopenic mice induces autoimmunity(3,4). Interleukin ( IL)-2 signaling is required for thymic development(5), peripheral expansion(6) and suppressive activity of T(reg)cells(7). Animals lacking IL-2 die of autoimmunity(8,9), which is prevented by administration of IL-2-responsive T(reg)cells(5). In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain T-reg cells(10), the question arises as to the effects of IL-2 therapy on them. We monitored Treg cells during immune reconstitution in individuals with cancer who did or did not receive IL-2 therapy. CD4(+)CD25(hi) cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the T-reg cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent T-reg cells in normal hosts, and IL-2 induced T-reg cell expansion was further augmented by lymphopenia. On a per-cell basis, T-reg cells generated by IL-2 therapy expressed similar levels of FOXP3 and had similar potency for suppression compared to Treg cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4(+)CD25(+) T-reg cell homeostasis.