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 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.