Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells

Nat Immunol. 2010 Sep;11(9):862-71. doi: 10.1038/ni.1917. Epub 2010 Aug 8.


In this study we demonstrate a new form of immunoregulation: engagement on CD4(+) T cells of the complement regulator CD46 promoted the effector potential of T helper type 1 cells (T(H)1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a regulatory phenotype, attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4(+) T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4(+) T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-gamma (IFN-gamma). Finally, gammadelta T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) gammadelta and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CHO Cells
  • Cells, Cultured
  • Complement Activating Enzymes / immunology
  • Cricetinae
  • Cricetulus
  • Cytokines / immunology*
  • Gene Expression Regulation* / drug effects
  • Humans
  • Interleukin-10 / immunology
  • Interleukin-2 / immunology
  • Jurkat Cells
  • Membrane Cofactor Protein / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology


  • Antibodies, Monoclonal
  • CD46 protein, human
  • Cytokines
  • Interleukin-2
  • Membrane Cofactor Protein
  • Interleukin-10
  • Complement Activating Enzymes