Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

Eur J Immunol. 2011 Jun;41(6):1539-49. doi: 10.1002/eji.201040993. Epub 2011 May 25.

Abstract

We show that the T-cell immunoglobalin mucin, Tim-1, initially reported to be expressed on CD4(+) T cells, is constitutively expressed on dendritic cells (DCs) and that its expression further increases after DC maturation. Tim-1 signaling into DCs upregulates costimulatory molecule expression and proinflammatory cytokine production, thereby promoting effector T-cell responses, while inhibiting Foxp3(+) Treg responses. By contrast, Tim-1 signaling in T cells only regulates Th2 responses. Using a high-avidity/agonistic anti-Tim-1 antibody as a co-adjuvant enhances the immunogenic function of DCs, decreases the suppressive function of Tregs, and substantially increases proinflammatory Th17 responses in vivo. The treatment with high- but not low-avidity anti-Tim-1 not only worsens experimental autoimmune encephalomyelitis (EAE) in susceptible mice but also breaks tolerance and induces EAE in a genetically resistant strain of mice. These findings indicate that Tim-1 has an important role in regulating DC function and thus shifts the balance between effector and regulatory T cells towards an enhanced immune response. By understanding the mechanisms by which Tim-1 regulates DC and T-cell responses, we may clarify the potential utility of Tim-1 as a target of therapy against autoimmunity, cancer, and infectious diseases.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Dendritic Cells / pathology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Hepatitis A Virus Cellular Receptor 1
  • Immunization
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Lymphocyte Activation
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Myelin Proteolipid Protein / immunology
  • Peptide Fragments / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Signal Transduction / immunology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Th1-Th2 Balance

Substances

  • Antibodies, Monoclonal
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Interleukin-17
  • Membrane Proteins
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta
  • myelin proteolipid protein (139-151)

Grant support