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首页> 外文期刊>Nature >TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation
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TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation

机译：TSLP促进独立于白介素3的嗜碱性粒细胞造血和2型炎症

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摘要

CD4~+ T-helper type 2 (T_H2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites~1 and promote the pathological inflammation associated with asthma and allergic diseases~2. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T_H2 cytokine-associated inflammatory diseases~(3-6). In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T_H2 cytokine-mediated immunity and inflammation~(5,7-12) However, the mechanisms through which TSLP induces T_H2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T_H2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcrip-tional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T_H2 cytokine-mediated inflammation.
机译：CD4〜+ T辅助2型（T_H2）细胞以表达白介素（IL）-4，IL-5，IL-9和IL-13为特征，是免疫寄生虫〜1并促进病理的必需条件与哮喘和过敏性疾病相关的炎症〜2。细胞因子胸腺基质淋巴细胞生成素（TSLP）编码基因的多态性与人类多种变态反应疾病的发展有关，这表明TSLP是与T_H2细胞因子相关的炎性疾病的关键调节因子[3-6]。为了支持基因分析，过度的TSLP产生与患者的哮喘，特应性皮炎和食物过敏有关，并且在鼠类系统中的研究表明TSLP促进T_H2细胞因子介导的免疫和炎症〜（5,7-12）然而，其机制TSLP诱导T_H2细胞因子反应的机制仍然不清楚。在这里，我们证明TSLP促进系统性嗜碱性粒细胞增多，TSLP-TSLPR相互作用的破坏导致有缺陷的嗜碱性粒细胞应答，并且TSLPR足够的嗜碱性粒细胞可以在体内恢复T_H2细胞依赖性免疫。 TSLP直接作用于骨髓驻留祖细胞以选择性促进嗜碱性粒细胞应答。至关重要的是，TSLP可以在IL-3-IL-3R充足和不足的环境中引发嗜碱性粒细胞应答，并且全基因组转录谱分析和功能分析确定了TSLP引发与IL-3引发的嗜碱性粒细胞之间的异质性。此外，活化的人类嗜碱性粒细胞表达TSLPR，从嗜酸性食管炎患者中分离出的嗜碱性粒细胞不同于经典嗜碱性粒细胞。总而言之，这些研究确定了嗜碱性粒细胞细胞谱系中以前无法识别的异质性，并表明TSLP的表达可能通过调节嗜碱性粒细胞的造血作用并引发功能上不同的嗜碱性粒细胞，从而促进多种过敏性疾病的发生，从而促进T_H2细胞因子介导的炎症。

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  • 来源
    《Nature》 |2011年第7363期|p.229-233|共5页
  • 作者

    Mark C. Siracusa; Steven A. Saenz; David A. Hill; Brian S. Kim; Mark B. Headley; Travis A. Doering; E. John Wherry; Heidi K. Jessup; Lori A. Siegel; Taku Kambayashi; Emily C. Dudek; Masato Kubo; Antonella Cianferoni; Jonathan M. Spergel; Steven F. Ziegler; Michael R. Comeau; David Artis;

  • 作者单位

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Immunology Program, Benaroya Research Institute, Seattle, Washington 98101, and Immunology Department, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Inflammation Research, Amgen Inc., Seattle, Washington 98119, USA;

    Inflammation Research, Amgen Inc., Seattle, Washington 98119, USA;

    Department of Pathology and Laboratory Medicine, Perelman School of Medicine,University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Division of Allergy and Immunology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine,University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan Division of Molecular Pathology, Research Institute for Biological Science, Tokyo University of Science, Chiba 278-0022, Japan;

    Division of Allergy and Immunology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine,University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Division of Allergy and Immunology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine,University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    Immunology Program, Benaroya Research Institute, Seattle, Washington 98101, and Immunology Department, University of Washington School of Medicine, Seattle, Washington 98195, USA;

    Inflammation Research, Amgen Inc., Seattle, Washington 98119, USA;

    Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

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