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 2

Regulatory and pathogenic T cell infiltration after adoptive transfer is driven by the sex of the transgenic donor cells and not by the recipient.

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Regulatory and pathogenic T cell infiltration after adoptive transfer is...
Immune cell infiltration was analyzed after adoptive transfer in recipient animals 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 and B) Absolute number of Vα8.3+Vβ4+ cells within CD4+ T lymphocytes or CD8+ T lymphocytes within the CNS of male and female SJL/j recipients at different disease phases after adoptive transfer of (A) female TCR1640 immune cells or (B) male TCR1640 immune cells. (C and D) Percentage of Vα8.3+Vβ4+ cells within CD4+ T lymphocytes or CD8+ T lymphocytes within the CNS of male and female SJL/j recipients at different disease phases after adoptive transfer of (A) female TCR1640 immune cells or (B) male TCR1640 immune cells. (E and F) Representative confocal images of CD4+ T lymphocyte infiltration into cerebellum, meninges, and ventricles within the CNS of male and female SJL/j recipients at different disease phases after adoptive transfer of (E) female TCR1640 immune cells or (F) male TCR1640 immune cells. (G and H) Representative confocal images of CD4+ T lymphocyte infiltration and infiltration of Foxp3+ cells into cerebellum of male and female SJL/j recipients at different disease phases after adoptive transfer of (G) female TCR1640 immune cells or (H) male TCR1640 immune cells. (I and J) Number of CD4+ and Foxp3+ cells from confocal images of cerebellum of male and female SJL/j recipients at different disease phases after adoptive transfer were counted and used to calculate the percentage of infiltrating Foxp3+ cells (at least 3 images were used per recipient). (K and L) Percentage of Th1 and Th17 lymphocytes in CNS of male and female SJL/j recipients at different disease phases after adoptive transfer of (K) male TCR1640 immune cells or (L) female TCR1640 immune cells. 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 was used. *P < 0.05, *** P < 0.001, **** P < 0.0001. Scale bar: 100 μm. P < 0.05 was considered significant