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 4

Development of progressive EAE and increased expression of CCL20 in DR2bΔR2 recipient mice.

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Development of progressive EAE and increased expression of CCL20 in DR2b...
(A) Schematic showing passive EAE induction of DR2b and DR2bΔR2 mice (recipients) by transferring MOG35-55–reactive T cells obtained from DR2b donors and expanded in vitro. (B) Clinical signs of EAE, (C) clinical signs of ataxia, and (D) change in weight were monitored daily in DR2b and DR2bΔR2 recipient mice after induction of adoptive transfer EAE with DR2b WT T cells. Representative data from 6 (B and C) and 3 (D) independent experiments with n = 4–8 mice per group. (E) CD4+ T cell numbers in CNS at acute disease stage. Representative data from 3 independent experiments with n = 3–5 mice per group. (F) Concentration of IL-17 in whole CNS tissue homogenate at acute disease. Pooled data from 3 independent experiments, n = 8 for DR2b and n = 9 for DR2bΔR2 recipient mice. (G) Frequencies of CD4+Foxp3+ T cells in CNS at onset (day 7 after transfer), acute (day 12 after transfer), and disease progression phase (day 15 after transfer). Representative data from 3 independent experiments with n = 3–5 mice per group. (H) Fold change of CCL20 in whole CNS tissue homogenate at days 12–15 after transfer (acute to progression phase) relative to the experimental mean expression. Pooled data of 3 independent experiments. n = 10 mice per group. (I) Ccl20 mRNA expression in CNS tissue homogenate at acute disease measured by real-time PCR (qPCR). Representative data from 3 independent experiments with n = 3–5 per group. (J) Ccr6 mRNA expression in CNS tissue homogenate at the progression phase measured by qPCR. Pooled data from 2 independent experiments with n = 6 per group. Statistical significance was determined by 2-way ANOVA and for multiple comparisons with Holm-Šídák correction (B–D) or Student’s 2-tailed t test with Welch’s correction (E–J). *P ≤ 0.05; and ***P ≤ 0.001. Error bars indicate mean ± SD.