TCR-stimulated changes in cell surface CD46 expression generate type 1 regulatory T cells

Sci Signal. 2017 Oct 24;10(502):eaah6163. doi: 10.1126/scisignal.aah6163.


A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (TH1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells. We found that stimulation of the T cell receptor (TCR)-CD3 complex was associated with a reduction in the apparent molecular mass of CD46 in a manner that depended on O-glycosylation. CD3-stimulated changes in CD46 O-glycosylation status reduced CD46 processing and subsequent T cell signaling. During T cell activation, CD46 was recruited to the immune synapse in a manner that required its serine-, threonine-, and proline-rich (STP) region, which is rich in O-glycosylation sites. Recruitment of CD46 to the immune synapse switched T cells from producing the inflammatory cytokine interferon-γ (IFN-γ) to producing IL-10. Furthermore, CD4+ T cells isolated from MS patients did not exhibit a CD3-stimulated reduction in the mass of CD46 and thus showed increased amounts of cell surface CD46. Together, these data suggest a possible mechanism underlying the regulatory function of CD46 on T cells. Our findings may explain why this pathway is defective in patients with MS and provide insights into MS pathogenesis that could help to design future immunotherapies.

MeSH terms

  • Adult
  • CD3 Complex / metabolism
  • Female
  • Glycosylation
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Lymphocyte Activation*
  • Male
  • Membrane Cofactor Protein / genetics
  • Membrane Cofactor Protein / metabolism*
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Plasmids / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / immunology


  • CD3 Complex
  • CD46 protein, human
  • IL10 protein, human
  • Membrane Cofactor Protein
  • Receptors, Antigen, T-Cell
  • Interleukin-10
  • Interferon-gamma