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Nature. 2015 Jan 15;517(7534):386-90. doi: 10.1038/nature13848. Epub 2014 Oct 26.

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.

Author information

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.

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.

PMID:
25363763
PMCID:
PMC4297519
DOI:
10.1038/nature13848
[Indexed for MEDLINE]
Free PMC Article

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