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

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

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 4

Female and male TCR1640-transgenic immune cells have a different gene expression profile.

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Female and male TCR1640-transgenic immune cells have a different gene ex...
(A) RNA was isolated from immune cells that were Th1/Th17 differentiated and derived from female and male TCR1640-transgenic mice and from male and female SJL/j WT mice for gene expression analysis. (B) Differently expressed genes were hierarchically clustered, and the top 65 genes differentially expressed between male TCR1640-transgenic mice, female TCR1640-transgenic mice, male SJL/j WT mice, and female SJL/j WT mice were plotted as a heatmap. Blue indicates low relative expression, and red indicates high relative expression. Rows represent duplicate experiments. (C) Differently expressed genes were hierarchically clustered based on the following model: (TCR1640 female – SJL/j WT female)/(TCR1640 male – SJL/j WT male), and the top 33 genes were plotted as a heatmap. (D) GO analysis was performed on the data set described in C and shows the analysis of pathways that are significantly upregulated or downregulated in female TCR1640-transgenic mice. (E) Differently expressed genes of the pathway negative regulation of T cell–mediated immunity were hierarchically clustered and plotted as a heatmap.