TNFR2 limits proinflammatory astrocyte functions during EAE induced by pathogenic DR2b-restricted T cells
Itay Raphael, Francisco Gomez-Rivera, Rebecca A. Raphael, Rachel R. Robinson, Saisha Nalawade, Thomas G. Forsthuber
Itay Raphael, Francisco Gomez-Rivera, Rebecca A. Raphael, Rachel R. Robinson, Saisha Nalawade, Thomas G. Forsthuber
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Research Article Immunology

TNFR2 limits proinflammatory astrocyte functions during EAE induced by pathogenic DR2b-restricted T cells

Abstract

Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease where the underlying mechanisms driving disease progression have remained unresolved. HLA-DR2b (DRB1*15:01) is the most common genetic risk factor for MS. Additionally, TNF and its receptors TNFR1 and TNFR2 play key roles in MS and its preclinical animal model, experimental autoimmune encephalomyelitis (EAE). TNFR2 is believed to ameliorate CNS pathology by promoting remyelination and Treg function. Here, we show that transgenic mice expressing the human MHC class II (MHC-II) allele HLA-DR2b and lacking mouse MHC-II and TNFR2 molecules, herein called DR2bΔR2, developed progressive EAE, while disease was not progressive in DR2b littermates. Mechanistically, expression of the HLA-DR2b favored Th17 cell development, whereas T cell–independent TNFR2 expression was critical for restraining of an astrogliosis-induced proinflammatory milieu and Th17 cell responses, while promoting remyelination. Our data suggest the TNFR2 signaling pathway as a potentially novel mechanism for curtailing astrogliosis and promoting remyelination, thus providing new insights into mechanisms limiting progressive MS.

Authors

Itay Raphael, Francisco Gomez-Rivera, Rebecca A. Raphael, Rachel R. Robinson, Saisha Nalawade, Thomas G. Forsthuber

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Figure 1

Lack of TNFR2 expression promotes the development of progressive experimental autoimmune encephalomyelitis in HLA-DR2b–transgenic mice.

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Lack of TNFR2 expression promotes the development of progressive experim...
(A) C57BL/6 (B6) wild-type (WT), B6 TNFR2–/–, and B6 TNF–/– mice were immunized to induce experimental autoimmune encephalomyelitis (EAE). Clinical signs of EAE were monitored daily. Shown are mean clinical disease scores of representative results from 3–6 independent experiments with n = 5–12 mice per group. Statistical significance was determined by 1-way ANOVA corrected for FDR using Benjamini, Krieger, and Yekutieli method. (B) B6 WT and DR2b-transgenic mice were immunized with MOG35-55 peptide in CFA, and the frequencies of Ag-reactive IL-17–, GM-CSF–, and IFN-γ–producing T cells were measured in lymph nodes and spleens at day 9 after immunization. Pooled data from 3 independent experiments, n = 9–10 mice per group. (C) Percentage of CD4+Foxp3+ cells in naive WT B6 mice and naive DR2b mice. Pooled data from 2 independent experiments, n = 8 mice per group. Student’s 2-tailed t test with Welch’s correction. (D–H) DR2b (DR2b+/+ I-A–/–) and DR2bΔR2 (DR2b+/+ I-A–/– TNFR2–/–) were immunized to induce EAE. Shown are representative results from 3–6 independent experiments with n = 5–10 mice per group. (D) Clinical signs of EAE, (E) clinical signs of weight loss, and (F) clinical signs of ataxia were monitored daily. (G) EAE disease incidence and (H) clinical ataxia incidence were evaluated daily. Statistical significance was determined by multiple comparisons with Holm-Šídák correction (B, D–F). NS, not significant; *P ≤ 0.05; **P ≤ 0.01; and ***P ≤ 0.001. Error bars indicate mean ± standard deviation (SD).