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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors
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ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors

机译：ECM组件指导IL-10从效应记忆T细胞前体产生调节性T细胞（TR1）诱导

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摘要

We describe a role for ECM as a biosensor for inflammatory micro-environments that plays a critical role in peripheral immune tolerance. We show that hyaluronan (HA) promotes induction of Foxp3- IL-10-producing regulatory T cells (TR1) from conventional T-cell precursors in both murine and human systems. This is, to our knowledge, the first description of an ECM component inducing regulatory T cells. Intact HA, characteristic of healing tissues, promotes induction of TR1 capable of abrogating disease in an IL-10- dependent mouse colitis model whereas fragmentary HA, typical of inflamed tissues, does not, indicating a decisive role for tissue integrity in this system. The TR1 precursor cells in this system are CD4~+CD62L~-FoxP3~-, suggesting that effector memory cells assume a regulatory phenotype when they encounter their cognate antigen in the context of intact HA. Matrix integrity cues might thereby play a central role in maintaining peripheral tolerance. This TR1 induction is mediated by CD44 cross-linking and signaling through p38 and ERK1/2. This induction is suppressed, also in a CD44-dependent manner, by osteopontin, a component of chronically inflamed ECM, indicating that CD44 signaling serves as a nexus for fate decisions regarding TR1 induction. Finally, we demonstrate that TR1 induction signals can be recapitulated using synthetic matrices. These results reveal important roles for the matrix microenvironment in immune regulation and suggest unique strategies for immunomodulation.
机译：我们描述了ECM作为炎症微环境生物传感器的作用，该微环境在外周免疫耐受中起关键作用。我们显示透明质酸（HA）促进从常规T细胞前体在小鼠和人类系统中诱导产生Foxp3-IL-10产生的调节性T细胞（TR1）。就我们所知，这是诱导调节性T细胞的ECM成分的首次描述。完整的HA具有愈合组织的特征，在依赖IL-10的小鼠结肠炎模型中促进了能够消除疾病的TR1的诱导，而发炎组织中典型的片段性HA则没有，表明该系统中组织完整性的决定性作用。该系统中的TR1前体细胞是CD4 + CD62L--FoxP3--，这表明效应记忆细胞在完整HA的情况下遇到其关联抗原时会呈现出调节表型。基质完整性提示可能因此在维持周边耐受性方面发挥中心作用。这种TR1诱导是通过CD44交联和通过p38和ERK1 / 2进行信号传导介导的。骨桥蛋白（一种慢性发炎的ECM的成分）也以CD44依赖性的方式抑制了这种诱导，这表明CD44信号传导充当了关于TR1诱导的命运决定的纽带。最后，我们证明可以使用合成矩阵概括TR1感应信号。这些结果揭示了基质微环境在免疫调节中的重要作用，并提出了免疫调节的独特策略。

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    Paul L Bollyky; Rebecca P. Wu; Ben A. Falk; James D. Lord; S. Alice Long; Anton Preisinger; Brandon Teng; Gregory E. Holt; Nathan E. Standifer; Kathleen R. Braun; Cindy Fang Xie; Peter L. Samuels; Robert B. Vernon; John A. Gebe; Thomas N. Wight; Gerald T. Nepom;

  • 作者单位

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101,Division of Allergy and Infectious Diseases, University of Washington Medical Center,Seattle, WA 98195;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Division of Pulmonary, Critical Care and Sleep Medicine, University of Miami, Miami, FL 33136;

    Clinical Immunology, Amgen, Seattle,WA 98119-3105;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

    Benaroya Research Institute at Virginia Mason, Seattle, WA 98101;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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