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 3

Blood-brain barrier disruption is similar between female and male recipients after adoptive transfer of either male or female TCR1640-transgenic cells.

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Blood-brain barrier disruption is similar between female and male recipi...
Changes in blood-brain barrier kinetics were analyzed in recipient animals that were sacrificed at first peak of disease (acute, clinical score ≥3) for all transfers, at remission (clinical score of Δ ≥2) for injection of female transgenic cells, and during chronic disease for injection of male transgenic cells (stable clinical score ≥3 for more than 20 days). (A) Representative confocal images of fibrinogen extravasation and VCAM-1 expression in cerebellum, meninges, and ventricles of male and female SJL/j recipients after adoptive transfer of female (top) and male (bottom) TCR1640 immune cells. (B) Representative confocal images of fibrinogen extravasation and VCAM-1 expression in the cerebellum of male and female SJL/j recipients after adoptive transfer of female TCR1640 immune cells. (C) Representative confocal images of fibrinogen extravasation and VCAM-1 expression in the cerebellum of male and female SJL/j recipients at acute disease after adoptive transfer of male TCR1640 immune cells. Images are representative of independent experiments, with at least 3 animals per group. Scale bar: 100 μm. (D) Relative levels of expression for VCAM-1 and leakage of fibrinogen were determined by measuring the pixel intensity and area (n = 3–5 per vessel). Data are represented as mean ± SEM, and an unpaired 1-sided t test was used. P < 0.05 was considered significant.