• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >CEACAM1 regulates TIM-3-mediated tolerance and exhaustion
【24h】

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

机译：CEACAM1调节TIM-3介导的耐受性和疲劳

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

T-细胞调控是由若干种抑制性细胞表面分子如"T-细胞免疫球蛋白域和粘蛋白域-3"(TIM-3)介导的，后者是癌症免疫疗法的一个可能目标，此前曾被报告在由肿瘤诱导的免疫抑制中充当一个免疫检查点。然而，TIM-3诱导抗药性的配体此前尚未被发现，而且TIM-3在某些情况下还可能具有激发功能。这项研究发现，"癌胚抗原细胞粘附分子1"(CAECAM1)是鼠科动物TIM-3的异嗜性配体，是TIM-3介导抗药性和确保其达到最佳成熟度以及确保其细胞表面表达和调控功能等所需的。CEACAM1和TIM-3的同时阻断导致抗肿瘤免疫反应增强，在小鼠结肠直肠癌模型中肿瘤的消除效果得到提高。%T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in as through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-spedfic CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.
机译：T-细胞调控是由若干种抑制性细胞表面分子如"T-细胞免疫球蛋白域和粘蛋白域-3"(TIM-3)介导的，后者是癌症免疫疗法的一个可能目标，此前曾被报告在由肿瘤诱导的免疫抑制中充当一个免疫检查点。然而，TIM-3诱导抗药性的配体此前尚未被发现，而且TIM-3在某些情况下还可能具有激发功能。这项研究发现，"癌胚抗原细胞粘附分子1"(CAECAM1)是鼠科动物TIM-3的异嗜性配体，是TIM-3介导抗药性和确保其达到最佳成熟度以及确保其细胞表面表达和调控功能等所需的。CEACAM1和TIM-3的同时阻断导致抗肿瘤免疫反应增强，在小鼠结肠直肠癌模型中肿瘤的消除效果得到提高。%T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in as through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-spedfic CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.

著录项

  • 来源
    《Nature》 |2015年第7534期|386-390a5|共6页
  • 作者

    Yu-Hwa Huang; Chen Zhu; Yasuyuki Kondo; Ana C. Anderson; Amit Gandhi; Andrew Russell; Stephanie K. Dougan; Britt-Sabina Petersen; Espen Melum; Thomas Pertel; Kiera L. Clayton; Monika Raab; Qiang Chen; Nicole Beauchemin; Paul J. Yazaki; Michal Pyzik; Mario A. Ostrowski; Jonathan N. Glickman; Christopher E. Rudd; Hidde L. Ploegh; Andre Franke; Gregory A. Petsko; Vijay K. Kuchroo; Richard S. Blumberg;

  • 作者单位

    Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard, Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA;

    Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA;

    Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard, Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA;

    Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA;

    Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard, Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA;

    Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA;

    Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;

    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany;

    Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard, Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA,Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo 0424, Norway;

    Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA;

    Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada;

    Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK;

    State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;

    Goodman Cancer Research Centre, McGill University, Montreal H3G 1Y6, Canada;

    Beckman Institute, City of Hope, Duarte, California 91010, USA;

    Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard, Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA;

    Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada,Keenan Research Centre of St. Michael's Hospital, Toronto, Ontario M5S1A8, Canada;

    GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA;

    Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK;

    Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;

    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany;

    Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA;

    Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA;

    Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard, Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号