Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy

Immunity. 2004 Jan;20(1):107-18. doi: 10.1016/s1074-7613(03)00359-5.


Regulatory T cells play an important role in the maintenance of immunological self-tolerance by suppressing immune responses against autoimmune diseases and cancer. Little is known, however, about the nature of the physiological target antigens for CD4(+) regulatory T (Treg) cells. Here we report the identification of the LAGE1 protein as a ligand for tumor-specific CD4(+) Treg cell clones generated from the tumor-infiltrating lymphocytes (TILs) of cancer patients. Phenotypic and functional analyses demonstrated that they were antigen-specific CD4(+) Treg cells expressing CD25 and GITR molecules and possessing suppressive activity on the proliferative response of naive CD4(+) T cells to anti-CD3 antibody stimulation. Ligand-specific activation and cell-cell contact were required for TIL102 Treg cells to exert suppressive activity on CD4(+) effector cells. These findings suggest that the presence of tumor-specific CD4(+) Treg cells at tumor sites may have a profound effect on the inhibition of T cell responses against cancer.

MeSH terms

  • Antigens, Neoplasm*
  • Antigens, Surface
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Division / physiology
  • DNA-Binding Proteins / metabolism
  • Forkhead Transcription Factors
  • Humans
  • Immunotherapy*
  • Interferon-gamma / metabolism
  • Ligands
  • Membrane Proteins*
  • Neoplasms / immunology*
  • Phenotype
  • Proteins / genetics


  • Antigens, Neoplasm
  • Antigens, Surface
  • CTAG1B protein, human
  • CTAG2 protein, human
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Ligands
  • Membrane Proteins
  • Proteins
  • Interferon-gamma