Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6.
Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6.
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DOI：
10.4161/cc.8.9.8348
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Metcalfe SM
中科院分区：
文献类型：
--
作者：
Gao W;Thompson L;Zhou Q;Putheti P;Fahmy TM;Strom TB;Metcalfe SM
在免疫系统中，T 淋巴细胞具有区分“自身”和“非自身”的精湛能力。歧视性途径引导这些淋巴细胞分化为调节性 T 细胞 (Treg) 或效应性 T 细胞 (Teff)，其受到来自初始 T 细胞对同源抗原作出反应时的直接微环境的线索的影响。相互途径可能导致幼稚 T 细胞转变成保护性耐受性促进 Treg 或促炎 Th17 效应表型。 CD4+ 淋巴细胞的初次激活刺激其释放白血病抑制因子 (LIF)，并且 Treg 继续释放 LIF 以响应抗原，这意味着 LIF 在耐受中发挥作用。相比之下，白介素 6 (IL-6) 虽然与 LIF 密切相关，但可促进 Th17 细胞的成熟。在这里，我们表明 LIF 和 IL-6 在促进 Treg 和 Th17 谱系的承诺方面表现得截然相反。与 IL6 不同，LIF 支持 Foxp3（Treg 谱系转录因子）的表达，而 LIF 通过抑制 IL-6 诱导的 IL-17A 蛋白释放来对抗 IL6。与此形成鲜明对比的是，我们发现 IL6 有效抑制 LIF 信号传导，抑制 LIF 受体 gp190 的转录，并强烈诱导 axotropin/MARCH-7，这是一种新型 E3 泛素连接酶，我们发现它在 gp190 蛋白的降解中具有活性。在体内，抗 LIF 治疗减少了外源脾细胞受体中供体特异性 Treg。相反，针对 CD4 的单剂量可生物降解的 LIF 纳米颗粒成功地操纵了 LIF/IL6 轴，以开发供体特异性 Foxp3+ Treg。通过旁分泌将 LIF 递送至体内 CD4+ 细胞，从而利用内源性免疫调节，这对治疗的影响是深远的。
Within the immune system there is an exquisite ability to discriminate between “self ” and “non-self ” that is orchestrated by T lymphocytes. Discriminatory pathways guide differentiation of these lymphocytes into either regulatory (Treg) or effector (Teff) T cells, influenced by cues from the naïve T cell’s immediate micro-environment as it responds to cognate antigen. Reciprocal pathways may lead to commitment of naïve T cells into either the protective tolerance-promoting Treg, or to the pro-inflammatory Th17 effector phenotype. Primary activation of CD4+ lymphocytes stimulates their release of leukemia inhibitory factor (LIF), and Treg continue to release LIF in response to antigen, implying a role for LIF in tolerance. In contrast, interleukin-6 (IL-6), although very closely related to LIF, promotes maturation of Th17 cells. Here we show that LIF and IL-6 behave as polar opposites in promoting commitment to the Treg and Th17 lineages. Unlike IL6, LIF supported expression of Foxp3, the Treg lineage transcription factor, and LIF opposed IL6 by suppressing IL-6-induced IL-17A protein release. In striking contrast, we found that IL6 effectively inhibited LIF signalling, repressing transcription of the LIF receptor gp190, and strongly inducing axotrophin/MARCH-7, a novel E3 ubitquitin ligase that we discovered to be active in degradation of gp190 protein. In vivo, anti-LIF treatment reduced donor-specific Treg in recipients of foreign spleen cells. Conversely, a single dose of biodegradable LIF nanoparticles, targeted to CD4, successfully manipulated the LIF/IL6 axis towards development of donor-specific Foxp3+ Treg. The implications for therapy are profound, harnessing endogenous immune regulation by paracrine delivery of LIF to CD4+ cells in vivo.
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