IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis
Youjin Lee, Meike Mitsdoerffer, Sheng Xiao, Guangxiang Gu, Raymond A. Sobel, Vijay K. Kuchroo
Youjin Lee, Meike Mitsdoerffer, Sheng Xiao, Guangxiang Gu, Raymond A. Sobel, Vijay K. Kuchroo
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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 3

2D2xTH Il23r KO mice are resistant to developing spontaneous EAE.

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2D2xTH Il23r KO mice are resistant to developing spontaneous EAE. (A) Qu...
(A) Quantitative RT-PCR of Il22 and Il23r mRNA in Vα3.2+CD4+ T cells in the LNs and SP of 2D2xTH and 2D2xTH Il21r KO mice that developed EAE. (B) nCounter (Nanostring) analysis of 2D2 T cells sorted from 4-day–cultured LNs and splenocytes from 2D2xTH, 2D2xTH Il21r KO, and 2D2xTH Il23r KO mice. Cells were stimulated with either no rMOG (0 μg/ml) or rMOG (10 μg/ml) in vitro. (C) Flow cytometry analysis of annexin V and propidium iodide staining from 2D2 T cells or TH B cells that were cultured in vitro for 5 days with rMOG (10 μg/ml) from 2D2xTH, 2D2xTH Il21r KO, and 2D2xTH Il23r KO mice. (D) 3H proliferation assay of T cells from 2D2xTH, 2D2xTH Il21r KO, and 2D2xTH Il23r KO mice with various concentration of rMOG (0.01–10 μg/ml). (E) Incidence of spontaneous EAE from 2D2xTH (n = 63) and 2D2xTH Il23r KO (n = 50) (F) Quantification of the CNS lesions in the meninges and parenchyma of mice that developed spontaneous EAE. Data shown here are representative of 3 (A and B), 4 (D), or 5 (C) independent experiments with at least n = 3 mice unless otherwise indicated. Data represent mean ± SEM for A and D–F. ***P < 0.001.