Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus.
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.
Zeng
Defu
D
Division of Immunology & Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. dzeng@coh.org
Liu
Yinping
Y
Sidobre
Stephane
S
Kronenberg
Mitchell
M
Strober
Samuel
S
D000818:Animals; D018949:Antigens, CD1 / Q000032:analysis; D055610:Antigens, CD1d; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D018960:Hyaluronan Receptors / Q000032:analysis; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008177:Lupus Vulgaris / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008814:Mice, Inbred NZB; D018417:Th1 Cells / Q000276:immunology*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D018960:Hyaluronan Receptors; D007074:Immunoglobulin G; D007073:Immunoglobulin E; D007371:Interferon-gamma