New insights into differences in men’s and women’s immune systems

The results, published in the journal Nature Communications, reveal that women exhibit a stable pattern of X-chromosome gene inactivation during T-cell development.

“We observe that unexpectedly few genes on the X chromosome escape inactivation and that the inactivation remains stable during T-cell development. This provides new context for the sex differences seen in T-cell development and immune responses, where both genetic and hormonal factors likely play a role,” says Viktoria Hennings, a doctoral student in the Department of Pediatrics and co-first author of the article.

“Our findings challenge previous hypotheses regarding the dominant role of the X chromosome in explaining sex differences in the prevalence and severity of autoimmune and infectious diseases,” adds Christina Lundqvist, a researcher in the Department of Rheumatology and Inflammation Research and also a co-first author.

Broad impact of X-chromosome inactivation

Women have a more reactive immune system than men, offering strong protection against infectious diseases but also increasing their susceptibility to autoimmune diseases. These differences have previously been linked to incomplete X-chromosome inactivation and its effects on T cells—key immune cells in the body’s defense system.

In this study, researchers from the Sahlgrenska Academy in Gothenburg, in collaboration with researchers from Linköping University, created a high-resolution map of X-chromosome inactivation during the development of human T cells in the thymus.

The study demonstrates that this mechanism is far more stable than previously thought.

Challenging the hypothesis

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“We have shown that genes on the inactivated X chromosome do not ‘leak’ to the extent suggested by many earlier studies. This challenges a central hypothesis about why women have a more active immune system than men,” says Olov Ekwall, professor of pediatric immunology and co-senior author of the publication.

The study employed advanced genetic techniques, including RNA sequencing, whole-genome sequencing, and DNA methylation, to analyze samples from healthy boys and girls, a girl with Turner syndrome, and a girl with completely skewed X inactivation. The results indicate that T-cell development proceeds correctly regardless of whether girls have one or two X chromosomes—something previously thought to have significant implications.

The next step will be to investigate how the X chromosome influences T-cell activation, particularly in relation to autoimmune diseases such as lupus and multiple sclerosis.

Article Reference:: A landscape of 1 X-inactivation during human T cell development

Text: Elin Lindström