CD46-mediated costimulation induces a Th1-biased response and enhances early TCR/CD3 signaling in human CD4+ T lymphocytes

Eur J Immunol. 2004 Sep;34(9):2439-48. doi: 10.1002/eji.200324259.


The role of membrane cofactor protein (MCP, CD46) on human T cell activation has been analyzed. Coligation of CD3 and CD46 in the presence of PMA or CD28 costimuli enhanced IL-2, IFN-gamma, or IL-10 secretion by CD4+ T lymphocytes. The effect of CD46 on IL-10 secretion did not require additional costimuli like anti-CD28 antibodies or phorbol esters. CD46 also enhanced IL-2 or IFN-gamma secretion by CD4+ blasts. In contrast, IL-5 secretion was inhibited upon CD46-CD3 coligation, in all the cells analyzed. These effects were independent of IL-12 and suggest that CD46 costimulation promotes a Th1-biased response in human CD4+ T lymphocytes. CD46 enhanced TCR/CD3-induced tyrosine phosphorylation of CD3zeta and ZAP-70, as well as the activation of the ERK, JNK, and p38, but did not modify intracellular calcium. The effect of specific inhibitors shows that enhanced ERK activation contributes to augmented IFN-gamma and lower IL-5 secretion and, consequently, to the Th1 bias. Cross-linking CD46 alone induced weak tyrosine phosphorylation of CD3zeta and ZAP-70. However, CD46 cross-linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti-CD46 antibodies did not significantly alter TCR/CD3 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / physiology*
  • Cytokines / biosynthesis
  • Enzyme Activation
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation*
  • Lymphokines / biosynthesis
  • Membrane Cofactor Protein
  • Membrane Glycoproteins / physiology*
  • Membrane Proteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Receptor-CD3 Complex, Antigen, T-Cell / physiology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • Th1 Cells / physiology*
  • ZAP-70 Protein-Tyrosine Kinase


  • Antigens, CD
  • CD46 protein, human
  • Cytokines
  • Lymphokines
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • Membrane Proteins
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell
  • antigen T cell receptor, zeta chain
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Mitogen-Activated Protein Kinases