Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus
Defu Zeng, … , Mitchell Kronenberg, Samuel Strober
Defu Zeng, … , Mitchell Kronenberg, Samuel Strober
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1211-1222. https://doi.org/10.1172/JCI17165.
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Article Autoimmunity

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

Abstract

In vivo treatment of mice with the natural killer T (NKT) cell ligand, α-galactosylceramide (αGalCer), 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 αGalCer 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-αGalCer 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.

Authors

Defu Zeng, Yinping Liu, Stephane Sidobre, Mitchell Kronenberg, Samuel Strober

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Exacerbation or amelioration of lupus by αGalCer or anti-CD1d mAb treatm...
Exacerbation or amelioration of lupus by αGalCer or anti-CD1d mAb treatment in adult NZB/W mice. NZB/W mice were treated with αGalCer, PBS/vehicle, anti-CD1d mAb, and rat IgG2b isotype control. (a and b) Groups of 20-week-old NZB/W mice were given four injections of αGalCer or PBS/vehicle control at a dose of 4 μg/mouse over a period of 2 weeks. There were 15 mice in each group. In addition, groups of 8- to 12-week-old NZB/W mice were given 15 injections of anti-CD1d mAb or control rat IgG2b at a dose of 500 μg/mouse over a period of 6 months (five injections for the first month, two injections for each month thereafter). There were 20 mice in each group. All mice were monitored weekly for proteinuria (a) and survival (b). (c–e) The serum concentrations of IgE, IgG2a, and IgG2a anti-dsDNA Ab’s of the above-treated mice at the age of 26 weeks. Bars show means of 15 or 20 mice, and brackets show standard errors.