IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
复制标题
DOI：
10.1371/journal.ppat.1003293
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Couper KN
中科院分区：
文献类型：
--
作者：
Villegas-Mendez A;de Souza JB;Lavelle SW;Gwyer Findlay E;Shaw TN;van Rooijen N;Saris CJ;Hunter CA;Riley EM;Couper KN
在许多不同的炎症条件下，IL-27R，即WSX-1，需要限制效应CD4+ T细胞产生IFN-γ，但在感染期间，体内WSX-1介导的Th1反应调节的分子基础尚未得到详细研究。在这项研究中，我们证明了WSX-1信号在疟疾感染期间抑制致病性，终末分化（KLRG-1+） Th1细胞的发育，并建立了一个限制性阈值来限制紧急Th1反应。重要的是，我们发现WSX-1调节细胞对IL-12和IL-2的内在反应，但疟疾感染期间效应CD4+ T细胞池的命运主要通过IL-12依赖信号控制。最后，我们发现WSX-1通过独立于IL-10和Foxp3的机制调节疟疾感染过程中Th1细胞的末端分化；在WT、IL-10R1−/−和IL-10−/−小鼠中，Th1反应的动力学和强度以及Th1细胞末端分化的程度是相似的，而在WSX-1−/−小鼠中，Foxp3+细胞的数量和表型在感染期间基本没有改变。正如预期的那样，在疟疾感染期间，Foxp3+细胞的缺失并没有增强Th1细胞的极化或终末分化。我们的研究结果显著扩展了我们对IL-27在体内炎症条件下如何调节Th1反应的理解，并确定WSX-1是疟疾感染期间紧急Th1效应反应的关键和非冗余调节因子。细胞因子白介素27 （IL-27）是IL-12家族的一员，由先天免疫系统的细胞产生，并已被证明在广泛的炎症条件下发挥主要抑制作用，包括疟疾感染，在那里它抑制CD4+ T细胞依赖性免疫病理的发展。在这项研究中，我们发现IL-27通过阻止最终分化的Th1细胞的发展，抑制血液期疟疾感染期间CD4+ T细胞产生ifn - γ。我们研究了IL-27抑制终末分化Th1细胞形成的分子机制，发现它通过限制IL-12信号特异性地起作用。重要的是，我们证明了IL-27通过IL-10和Foxp3+调节性T细胞独立机制介导其对Th1应答的调节作用。因此，我们已经确定了一种新的途径，通过IL-27信号调节疟疾感染期间Th1反应的大小和质量，我们相信这将与许多其他促炎条件相关。因此，操纵IL-27通路可能是慢性炎症性疾病的一种可行的治疗方法。
The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4+ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1+) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4+ T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1−/− and IL-10−/− mice and the numbers and phenotype of Foxp3+ cells were largely unaltered in WSX-1−/− mice during infection. As expected, depletion of Foxp3+ cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection. The cytokine interleukin 27 (IL-27), a member of the IL-12 family, is produced by cells of the innate immune system and has been shown to exert mainly suppressive effects during a wide range of inflammatory conditions, including malaria infection, where it suppresses the development of CD4+ T cell-dependent immunopathology. In this study we show that IL-27 suppresses the production of IFN-gamma by CD4+ T cells during blood stage malaria infection by preventing the development of terminally differentiated Th1 cells. We investigated the molecular mechanisms by which IL-27 inhibits the formation of terminally differentiated Th1 cells and found that it does so specifically by restricting IL-12 signals. Importantly, we demonstrate that IL-27 mediates its regulatory effects on the Th1 response through IL-10 and Foxp3+ regulatory T cell independent mechanisms. Thus, we have identified a new pathway though which IL-27 signalling regulates the size and quality of the Th1 response during malaria infection, which we believe will have relevance to many other pro-inflammatory conditions. Manipulation of the IL-27 pathway may therefore represent an amenable therapeutic approach during chronic inflammatory disorders.
登录
查看更多内容
DOI：
10.1084/jem.20100410
发表时间：
2011-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cox JH;Kljavin NM;Ramamoorthi N;Diehl L;Batten M;Ghilardi N
通讯作者：
Ghilardi N
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.4
作者：
Diveu, Caroline;McGeachy, Mandy J.;Kastelein, Robert A.
通讯作者：
Kastelein, Robert A.
影响因子：
32.4
作者：
Hamano, S;Himeno, K;Yoshida, H
通讯作者：
Yoshida, H
IL-27 通过细胞因子信号转导抑制因子 3 抑制 CD28 介导的 IL-2 生成
影响因子：
4.4
作者：
Owaki, Toshiyuki;Asakawa, Masayuki;Yoshimoto, Takayuki
通讯作者：
Yoshimoto, Takayuki