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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 Article has an altmetric score of 3

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

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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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Figure 5

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Multicolor flow-cytometric analyses of spleen cells. Spleen cells from 8...
Multicolor flow-cytometric analyses of spleen cells. Spleen cells from 8- to 12-week-old C57BL/6 and NZB/W mice were stained with anti-TCRαβ, CD4, NK1.1, and CD1d-αGalCer tetramer. (a and e) Staining of CD4 versus TCRαβ for both strains. (b and f) NK1.1 versus TCRαβ on gated TCRαβ– cells. (c and g) NK1.1 versus TCRαβ on gated TCRαβ+ cells. (d and h) Tetramer versus TCRαβ on gated TCRαβ+ cells. (i and m) gated TCRαβ+CD4+ T cells were analyzed for CD4 versus tetramer. (j and n) Tetramer versus NK1.1 on gated TCRαβ+CD4+tetramer-positive cells. (k and o) NK1.1 versus CD4 on the gated TCRαβ+CD4+ cells. (l and p) NK1.1 versus tetramer on the gated TCRαβ+CD4+NK1.1+ cells. The percentage of each subset was shown beside the gating box. Data were representative of six mice in each strain. (q and t) Gated TCRαβ+CD4+ T cells were analyzed for CD4 versus tetramer. (r and s) Expression of CD69 and CD44, respectively, on the gated C57BL/6 cells and (u and v) expression of CD69 and CD44 on the gated NZB/W cells. The background staining with control CD1d-vehicle-tetramer for the gated T cells was less than 0.1%.

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