Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype

Nature. 2003 Jan 23;421(6921):388-92. doi: 10.1038/nature01315.


The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.

MeSH terms

  • Antigens, CD / metabolism*
  • CD3 Complex / metabolism*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Division
  • Cells, Cultured
  • Flow Cytometry
  • Humans
  • Immune Tolerance
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-2 / immunology
  • Interleukin-4 / metabolism
  • Lymphocyte Activation*
  • Membrane Cofactor Protein
  • Membrane Glycoproteins / metabolism*
  • Phenotype
  • Transforming Growth Factor beta / metabolism


  • Antigens, CD
  • CD3 Complex
  • CD46 protein, human
  • Interleukin-2
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma