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Sex-dependent factors encoded in the immune compartment dictate relapsing or progressive phenotype in demyelinating disease
Tessa Dhaeze, … , Stephanie Zandee, Alexandre Prat
Tessa Dhaeze, … , Stephanie Zandee, Alexandre Prat
Published March 21, 2019
Citation Information: JCI Insight. 2019;4(6):e124885. https://doi.org/10.1172/jci.insight.124885.
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Research Article Neuroscience

Sex-dependent factors encoded in the immune compartment dictate relapsing or progressive phenotype in demyelinating disease

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Abstract

TCR1640 mice, which have a T cell receptor (TCR) directed against MOG92–106, spontaneously develop experimental autoimmune encephalomyelitis. Female mice mostly develop a relapsing-remitting (RR) course and have a higher incidence of disease, while males most frequently suffer from progressive disease, reflecting the unresolved clinical sex discrepancies seen in multiple sclerosis. Herein, we performed adoptive transfers of male and female TCR1640 immune cells into WT animals to investigate if disease course is dependent on the sex of the donor immune cells or on the sex of the recipient animal. We found that transfer of female TCR1640 immune cells led to a RR disease while transfer of male TCR1640 immune cells led to a progressive course, independent of the sex of the recipient. In addition, regulatory and pathogenic T cell infiltration after transfer was also immune cell sex intrinsic. We performed genetic profiling of the donor immune cells and found significant differences between the transcriptomic profiles of male and female TCR1640 immune cells, interestingly, within genes related to immune regulation of T lymphocytes. These results suggest that differences in gene expression profiles related to regulation of T cell immunity seen in male and female neuroinflammatory disease drive relapsing versus progressive disease course.

Authors

Tessa Dhaeze, Catherine Lachance, Laurence Tremblay, Camille Grasmuck, Lyne Bourbonnière, Sandra Larouche, Olivia Saint-Laurent, Marc-André Lécuyer, Rose-Marie Rébillard, Stephanie Zandee, Alexandre Prat

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Figure 1

Disease course after adoptive transfer with transgenic TCR1640 immune cells is dependent on the sex of the donor.

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Disease course after adoptive transfer with transgenic TCR1640 immune ce...
(A) Overview of adoptive transfer where immune cells were isolated from spleens and lymph nodes of female and male TCR1640-transgenic mice and WT SJL/j mice and differentiated toward a Th1/Th17 phenotype and were injected into WT SJL/j female and male recipients. (B–D) Analysis of immune cells isolated from female and male TCR1640-transgenic and WT SJL/j mice and used for adoptive transfer. (B) Proportion of CD4+ and CD8+ T lymphocytes present in immune cells from TCR1640-transgenic and WT SJL/j mice (n ≥ 5 for each). (C) Average and representative dot plot of Vα8.3+Vβ4+ cells within CD4+ T lymphocytes from TCR1640-transgenic and WT SJL/j mice (n ≥ 5 for each). (D) Representative FACS dot plot and average of Th1-, Th17-, and GM-CSF–producing cells and relative mRNA expression of Foxp3 (by qPCR) in female and male TCR1640-transgenic mice (n ≥ 4 for each). (E) Clinical disease courses of representative recipients after adoptive transfer with TCR1640 immune cells (─) or WT SJL/j immune cells (- - -) into WT SJL/j in different conditions (female into female, female into male, male into male and male into female). Graphs are representative of more than 3 independent experiments. (F) Number of recoveries to a clinical score of 0/1 counted in different adoptive transfer conditions. (G) Number of relapses (clinical score of Δ ≥2) counted in different adoptive transfer conditions. (H) Histological analysis using Luxol fast blue and counterstained by H&E of cerebellum of SJL/j female and male recipients after adoptive transfer. After injection of female TCR1640 immune cells, recipients were sacrificed at acute disease (first peak, score ≥3) and during remission (clinical score of Δ ≥2). After injection of male TCR1640 immune cells, recipients were sacrificed at acute disease (score ≥3) and during chronic disease (clinical score ≥3 for more than 20 days). Histological analysis of cerebellum of SJL/j injected mice was performed as a control. Scale bar: 100 μm (white); 250 μm (black). Data are representative of 3 or more independent experiments, with at least 3 mice per group. Data are represented as mean ± SEM, and an unpaired 1-sided t test or 1-way ANOVA was used. **P < 0.01, **** P < 0.0001. P < 0.05 was considered significant.

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