Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis

Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5941-6. doi: 10.1073/pnas.0601335103. Epub 2006 Apr 3.


Administration of daclizumab, a humanized mAb directed against the IL-2Ralpha chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4(+) T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4(+) and CD8(+) T cells and significant expansion of CD56(bright) natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56(bright) NK cells and contraction of CD4(+) and CD8(+) T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56(bright) NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD / immunology
  • CD56 Antigen / immunology*
  • Daclizumab
  • Disease Models, Animal
  • Humans
  • Immunoglobulin G / therapeutic use*
  • Immunosuppressive Agents / therapeutic use
  • Inflammation / immunology
  • Interleukin-2 / deficiency
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor alpha Subunit
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation
  • Lymphocyte Subsets
  • Mice
  • Mice, Knockout
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / immunology
  • Receptors, Interleukin-2 / immunology*
  • T-Lymphocytes / immunology*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • CD56 Antigen
  • IL2RA protein, human
  • Il2ra protein, mouse
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Interleukin-2
  • Daclizumab