CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / chemistry
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • Autoimmunity / immunology
  • Cell Adhesion Molecules / chemistry
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Colorectal Neoplasms / immunology
  • Disease Models, Animal
  • Female
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immune Tolerance / immunology*
  • Inflammation / immunology
  • Inflammation / pathology
  • Ligands
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Molecular
  • Mucous Membrane / immunology
  • Mucous Membrane / pathology
  • Protein Conformation
  • Protein Multimerization
  • Receptors, Virus / chemistry
  • Receptors, Virus / immunology
  • Receptors, Virus / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, CD
  • CD66 antigens
  • Cell Adhesion Molecules
  • HAVCR2 protein, human
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Ligands
  • Membrane Proteins
  • Receptors, Virus