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首页> 外文期刊>Cell cycle >Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6.
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Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6.

机译：Treg与Th17淋巴细胞谱系由LIF与IL-6交叉调控。

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Within the immune system there is an exquisite ability to discriminate between self pathways guide differentiation of these lymphocytes into either regulatory (Treg) or effector (Teff) T cells, influenced by cues from the naive T cell's immediate micro-environment as it responds to cognate antigen. Reciprocal pathways may lead to commitment of naive 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.
机译：在免疫系统内，具有区分自身途径的精湛能力，这些途径会引导这些淋巴细胞分化为调节性（Treg）或效应器（Teff）T细胞，这受幼稚T细胞在其对同源细胞反应时的即时微环境提示的影响抗原。相互的通路可能导致幼稚T细胞进入保护性耐受性Treg或促炎性Th17效应子表型。 CD4（+）淋巴细胞的初级激活刺激其白血病抑制因子（LIF）的释放，并且Treg响应抗原而继续释放LIF，这暗示LIF在耐受性中的作用。相反，白细胞介素-6（IL-6）尽管与LIF密切相关，但可促进Th17细胞的成熟。在这里，我们显示LIF和IL-6在促进对Treg和Th17谱系的承诺方面表现为两极对立。与IL6不同，LIF支持Foxp3，Treg谱系转录因子的表达，并且LIF通过抑制IL-6诱导的IL-17A蛋白释放来对抗IL6。与之形成鲜明对比的是，我们发现IL6有效抑制LIF信号传导，抑制LIF受体gp190的转录，并强烈诱导促轴蛋白/ MARCH-7（一种新型的E3泛素连接酶），我们发现它对gp190蛋白的降解具有活性。在体内，抗LIF处理可降低外来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LIF纳米颗粒成功地操纵了LIF / IL6轴，朝着供体特异性Foxp3（+）Treg的发展发展。该疗法的意义深远，它通过将LIF旁分泌递送至体内CD4（+）细胞来利用内源性免疫调节。

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