2. Academic Validation
  3. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

  • Nature. 2015 Jan 15;517(7534):386-90. doi: 10.1038/nature13848.
Yu-Hwa Huang 1,  Chen Zhu 2,  Yasuyuki Kondo 1,  Ana C Anderson 2,  Amit Gandhi 1,  Andrew Russell 3,  Stephanie K Dougan 4,  Britt-Sabina Petersen 5,  Espen Melum 6,  Thomas Pertel 2,  Kiera L Clayton 7,  Monika Raab 8,  Qiang Chen 9,  Nicole Beauchemin 10,  Paul J Yazaki 11,  Michal Pyzik 1,  Mario A Ostrowski 12,  Jonathan N Glickman 13,  Christopher E Rudd 8,  Hidde L Ploegh 4,  Andre Franke 5,  Gregory A Petsko 3,  Vijay K Kuchroo 2,  Richard S Blumberg 1
Affiliations

Affiliations

  • 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 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.
  • 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.
  • 10 Goodman Cancer Research Centre, McGill University, Montreal H3G 1Y6, Canada.
  • 11 Beckman Institute, City of Hope, Duarte, California 91010, USA.
  • 12 1] Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada [2] Keenan Research Centre of St. Michael's Hospital, Toronto, Ontario M5S1A8, Canada.
  • 13 GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.
PMID: 25363763 DOI: 10.1038/nature13848
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.

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