机构：[1]Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.[2]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.[3]Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA.[4]Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.[5]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.[6]Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo 0424, Norway.[7]Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada.[8]Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.[9]State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[10]Goodman Cancer Research Centre, McGill University,MontrealH3G1Y6, Canada.[11]Beckman Institute, City ofHope,Duarte,California91010,USA.[12]Keenan ResearchCentre of St. Michael’sHospital, Toronto,OntarioM5S1A8, Canada.[13]GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.
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 cis 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-specific 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.
基金：
This work was supported by the American
Cancer Society grant RSG-11-057-01-LIB (A.C.A.); the Norwegian PSC research center
and the Unger Vetlesen Medical Fund (E.M.); Crohn’s & Colitis Foundation of America
fellowship grant (Y.-H.H.); Deutsche Forschungsgemeinschaft (DFG) Cluster of
Excellence ‘Inflammation at Interfaces’ Award (A.F. and B.-S.P.); Harvard Clinical
Translational Science Center, UL1 TR001102 (R. Gali); the National Basic Research
Program of China No. 2010CB529906 (Q.C.); Canadian Institute of Health Research
(K.L.C. and N.B.); Canadian Institute of Health Research grant MOP-93787 (M.A.O.);
AACR-Pancreatic Cancer Action Network (H.L.P. and S.K.D.); National Institutes of
Health (NIH) grant GM32415 (G.A.P.); NIH grants AI073748, NS045937, AI039671
and AI056299 (V.K.K.); NIH grants DK044319, DK051362, DK053056, DK088199,
the Harvard Digestive Diseases Center (HDDC) DK0034854 and High Point
Foundation (R.S.B.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
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最新[2023]版：
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第一作者：
第一作者机构：[1]Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
通讯作者：
推荐引用方式(GB/T 7714)：
Yu-Hwa Huang,Chen Zhu,Yasuyuki Kondo,et al.CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.[J].Nature.2015,517(7534):386-90.doi:10.1038/nature13848.
APA：
Yu-Hwa Huang,Chen Zhu,Yasuyuki Kondo,Ana C. Anderson,Amit Gandhi...&Richard S. Blumberg.(2015).CEACAM1 regulates TIM-3-mediated tolerance and exhaustion..Nature,517,(7534)
MLA：
Yu-Hwa Huang,et al."CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.".Nature 517..7534(2015):386-90
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