IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis
Youjin Lee, … , Raymond A. Sobel, Vijay K. Kuchroo
Youjin Lee, … , Raymond A. Sobel, Vijay K. Kuchroo
Published September 28, 2015
Citation Information: J Clin Invest. 2015;125(11):4011-4020. https://doi.org/10.1172/JCI75933.
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Research Article Immunology

IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis

Abstract

IL-17–producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21–mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity.

Authors

Youjin Lee, Meike Mitsdoerffer, Sheng Xiao, Guangxiang Gu, Raymond A. Sobel, Vijay K. Kuchroo

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Figure 1

2D2xTH Il21r KO mice have decreased incidence of spontaneous EAE.

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2D2xTH Il21r KO mice have decreased incidence of spontaneous EAE. (A) Qu...
(A) Quantitative RT-PCR from 2D2 T cells sorted from the CNS, LNs, and SP of 2D2xTH mice that developed EAE. (B) Incidence of EAE from 2D2xTH (n = 63) and 2D2xTH Il21r KO (n = 43) mice. Statistical analysis by linear regression curve was graphed with the 95% confidence band of the regression line. (C) Quantification of the CNS lesions. (D and E) Paraffin sections of the spinal cord from indicated mice at the peak of disease stained with luxol fast blue and H&E. Meningeal and parenchymal inflammatory infiltrates and meningeal lymphoid follicles are shown (arrows). Inset in D is shown at ×10 magnification in lower panel. Scale bars: 200 μm (D, upper panel; E); 20 μm (D, lower panel). (F) Quantification of meningeal lymphoid aggregates in the CNS from 2D2xTH (n = 7) and 2D2xTH Il21r KO (n = 5) mice that developed EAE. (G) Intracellular cytokine staining of IFN-γ and IL-17 from 2D2 T cells in the CNS from indicated mice that developed EAE. (H) Quantitative RT-PCR of 2D2 T cells isolated from the LNs and SP from indicated mice that developed EAE (n = 3). (I) Intracellular cytokine staining of IFN-γ and IL-17 from naive CD4+ T cells from 2D2xTH and 2D2xTH Il21r KO mice differentiated for 4 days in vitro with no cytokines (Th0), IL-12 (Th1), and TGF-β3/IL-6 (Th17). (J) Quantitative RT-PCR from 2D2 T cells that were differentiated with TGF-β3/IL-6 (Th17) for 4 days in vitro. Statistics were determined by 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001. Data shown are representative of 3 (A–H) or 4 (I and J) total experiments. Data represent mean ± SEM for figures A–C, F, H, and K. A represents pooled samples from n = 3 mice for each experiment.