Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling

Nat Rev Immunol. 2003 Jul;3(7):544-56. doi: 10.1038/nri1131.


Many studies have shown the central importance of the co-receptors CD28, inducible costimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) in the regulation of many aspects of T-cell function. CD28 and ICOS have both overlapping and distinct functions in the positive regulation of T-cell responses, whereas CTLA4 negatively regulates the response. The signalling pathways that underlie the function of each of the co-receptors indicate their shared and unique properties and provide compelling hints of functions that are as yet uncovered. Here, we outline the shared and distinct signalling events that are associated with each of the co-receptors and provide unifying concepts that are related to signalling functions of these co-receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Abatacept
  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • CD28 Antigens / immunology*
  • Cell Cycle Proteins*
  • Humans
  • Immunoconjugates / immunology*
  • Inducible T-Cell Co-Stimulator Protein
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase Kinase 1*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Molecular Sequence Data
  • NF-kappa B / biosynthesis
  • Phosphatidylinositol 3-Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-vav
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*


  • Antigens, Differentiation, T-Lymphocyte
  • CD28 Antigens
  • Cell Cycle Proteins
  • ICOS protein, human
  • Immunoconjugates
  • Inducible T-Cell Co-Stimulator Protein
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • VAV1 protein, human
  • Abatacept
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases