CXCR3-dependent CD4⁺ T cells are required to activate inflammatory monocytes for defense against intestinal infection.
CXCR3-dependent CD4⁺ T cells are required to activate inflammatory monocytes for defense against intestinal infection.
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DOI：
10.1371/journal.ppat.1003706
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Denkers EY
中科院分区：
文献类型：
--
作者：
Cohen SB;Maurer KJ;Egan CE;Oghumu S;Satoskar AR;Denkers EY
趋化因子及其受体在协调对微生物病原体的免疫中发挥关键作用，包括口服获得的th1诱导原生动物寄生虫弓形虫。趋化因子受体CXCR3与Th1应答相关，在这里，我们使用双链CXCR3- egfp敲入报告小鼠来证明在弓形虫感染期间该趋化因子受体在CD4+和CD8+ T淋巴细胞上的上调。我们发现CXCR3在肠黏膜对寄生虫的抗性中起关键作用。在Cxcr3−/−小鼠中缺乏受体导致在固有层室中特异性控制弓形虫的能力选择性丧失。CD4+ T细胞在肠固有层的募集和刺激时分泌IFN-γ的能力均受损。CD11b+Ly6C/G+炎性单核细胞的局部募集，最近报道是肠道中主要的抗弓形虫效应物，不受CXCR3缺失的影响。然而，通过TNF-α和IL-12的双重产生来测量的炎症单核细胞激活状态在Cxcr3−/−小鼠中严重受损。引人注目的是，在感染前将野生型而非Ifnγ−/−CD4+ T淋巴细胞过继转移到Cxcr3−/−动物体内，纠正了炎性巨噬细胞激活的缺陷，同时逆转了敲除动物的易感性表型。我们的研究结果确定了CXCR3在协调先天免疫和适应性免疫中的核心作用，确保Th1效应物的产生和它们的运输到感染的前线，以编程炎症单核细胞的微生物杀伤。近年来，炎性单核细胞已成为肠道防御肠道病原体的重要效应器，但对其激活的要求尚不明确。本研究以弓形虫（一种经口获得的th1诱导病原体）为研究对象，研究肠黏膜中炎性巨噬细胞激活的条件。我们发现CD4+ T淋巴细胞依赖于趋化因子受体CXCR3的表达而募集，通过分泌IFN-γ介导肠黏膜炎性单核细胞的激活，进而控制感染。因此，CXCR3在T淋巴细胞和炎症单核细胞效应物之间起着协调抗微生物通讯的关键作用。
Chemokines and their receptors play a critical role in orchestrating immunity to microbial pathogens, including the orally acquired Th1-inducing protozoan parasite Toxoplasma gondii. Chemokine receptor CXCR3 is associated with Th1 responses, and here we use bicistronic CXCR3-eGFP knock-in reporter mice to demonstrate upregulation of this chemokine receptor on CD4+ and CD8+ T lymphocytes during Toxoplasma infection. We show a critical role for CXCR3 in resistance to the parasite in the intestinal mucosa. Absence of the receptor in Cxcr3−/− mice resulted in selective loss of ability to control T. gondii specifically in the lamina propria compartment. CD4+ T cells were impaired both in their recruitment to the intestinal lamina propria and in their ability to secrete IFN-γ upon stimulation. Local recruitment of CD11b+Ly6C/G+ inflammatory monocytes, recently reported to be major anti-Toxoplasma effectors in the intestine, was not impacted by loss of CXCR3. However, inflammatory monocyte activation status, as measured by dual production of TNF-α and IL-12, was severely impaired in Cxcr3−/− mice. Strikingly, adoptive transfer of wild-type but not Ifnγ−/− CD4+ T lymphocytes into Cxcr3−/− animals prior to infection corrected the defect in inflammatory macrophage activation, simultaneously reversing the susceptibility phenotype of the knockout animals. Our results establish a central role for CXCR3 in coordinating innate and adaptive immunity, ensuring generation of Th1 effectors and their trafficking to the frontline of infection to program microbial killing by inflammatory monocytes. Inflammatory monocytes have recently emerged as important effectors in intestinal defense against enteric pathogens, but requirements for their activation are poorly defined. Here we use the protozoan Toxoplasma gondii, an orally acquired Th1-inducing pathogen, to study the requirements for inflammatory macrophage activation in the intestinal mucosa. We find that CD4+ T lymphocytes, recruited in dependence upon their expression of the chemokine receptor CXCR3, mediate activation of intestinal mucosa inflammatory monocytes via secretion of IFN-γ, in turn resulting in control of infection. Thus, CXCR3 functions as a critical lynchpin coordinating anti-microbial communication between T lymphocytes and inflammatory monocyte effectors.
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影响因子：
3.4
作者：
Khaminets A;Hunn JP;Könen-Waisman S;Zhao YO;Preukschat D;Coers J;Boyle JP;Ong YC;Boothroyd JC;Reichmann G;Howard JC
通讯作者：
Howard JC
影响因子：
64.8
作者：
Harris, Tajie H.;Banigan, Edward J.;Christian, David A.;Konradt, Christoph;Wojno, Elia D. Tait;Norose, Kazumi;Wilson, Emma H.;John, Beena;Weninger, Wolfgang;Luster, Andrew D.;Liu, Andrea J.;Hunter, Christopher A.
通讯作者：
Hunter, Christopher A.
影响因子：
29.4
作者：
Buzoni-Gatel, D;Debbabi, H;Kasper, LH
通讯作者：
Kasper, LH
影响因子：
32.4
作者：
Groom JR;Richmond J;Murooka TT;Sorensen EW;Sung JH;Bankert K;von Andrian UH;Moon JJ;Mempel TR;Luster AD
通讯作者：
Luster AD
影响因子：
3.7
作者：
Groom JR;Luster AD
通讯作者：
Luster AD