Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus

J Clin Invest. 2003 Oct;112(8):1211-22. doi: 10.1172/JCI17165.


In vivo treatment of mice with the natural killer T (NKT) cell ligand, alpha-galactosylceramide (alphaGalCer), ameliorates autoimmune diabetes and experimental autoimmune encephalomyelitis (EAE) by shifting pathogenic Th1-type immune responses to nonpathogenic Th2-type responses. In the current study, in vivo activation of NKT cells in adult NZB/W mice by multiple injections of alphaGalCer induced an abnormal Th1-type immune response as compared with the Th2-type response observed in nonautoimmune C57BL/6 mice. This resulted in decreased serum levels of IgE, increased levels of IgG2a and IgG2a anti-double-stranded DNA (anti-dsDNA) Ab's, and exacerbated lupus. Conversely, treatment of NZB/W mice with blocking anti-CD1d mAb augmented Th2-type responses, increased serum levels of IgE, decreased levels of IgG2a and IgG2a anti-dsDNA Ab's, and ameliorated lupus. While total CD4+ T cells markedly augmented in vitro IgM anti-dsDNA Ab secretion by splenic B cells, the non-CD1d-reactive (CD1d-alphaGalCer tetramer-negative) CD4+ T cells (accounting for 95% of all CD4+ T cells) failed to augment Ab secretion. The CD1d-reactive tetramer-positive CD4+ T cells augmented anti-dsDNA Ab secretion about tenfold. In conclusion, activation of NKT cells augments Th1-type immune responses and autoantibody secretion that contribute to lupus development in adult NZB/W mice, and anti-CD1d mAb might be useful for treating lupus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD1 / analysis
  • Antigens, CD1d
  • CD4-Positive T-Lymphocytes / immunology
  • Female
  • Hyaluronan Receptors / analysis
  • Immunoglobulin E / blood
  • Immunoglobulin G / blood
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Lupus Vulgaris / etiology*
  • Lupus Vulgaris / immunology
  • Lupus Vulgaris / therapy
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred NZB
  • Th1 Cells / immunology*


  • Antigens, CD1
  • Antigens, CD1d
  • Hyaluronan Receptors
  • Immunoglobulin G
  • Immunoglobulin E
  • Interferon-gamma