title: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Yu-Hwa
authors.initials: YH
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: 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.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Gandhi
authors.affiliation: Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Russell
authors.affiliation: Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Dougan
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: 1] Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA [2] Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo 0424, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Kiera L
authors.initials: KL
authors.lastname: Clayton
authors.affiliation: Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Raab
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal H3G 1Y6, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.affiliation: Beckman Institute, City of Hope, Duarte, California 91010, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yazaki
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Pyzik
authors.affiliation: 1] Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada [2] Keenan Research Centre of St. Michael's Hospital, Toronto, Ontario M5S1A8, Canada.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.affiliation: GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.affiliation: Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
authors.affiliation: Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: 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.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D011487:Protein Conformation; D055503:Protein Multimerization; D011991:Receptors, Virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; C448908:HAVCR2 protein, human; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008024:Ligands; D008565:Membrane Proteins; D011991:Receptors, Virus