Sex Differences in Immune Responses May Come Down to One Gene

Why do men and women respond differently to infections, allergies and treatments?

Researchers at the University of York and Hull York Medical School asked this question in a study published in The Journal of Immunology.

They found that just one gene can shape how female immune cells behave, while male cells appear unaffected.

Sex differences in immunity extend beyond hormones and chromosomes

Biological sex shapes how the immune system works. Women are more likely to develop autoimmune and allergic conditions, while men are more likely to have severe infections. These sex differences raise practical problems: treatments often work better in one sex than the other, and we do not fully understand why.

One example of a common condition that has a large sex disparity is asthma, which affects ~250 million people worldwide – and yet ~60% of severe adult cases are found in women. Women also face a heavier burden of allergic disease and inflammatory conditions, suggesting that their immune cells may develop and respond differently.

Research has primarily focused on hormones and genes located on the X and Y chromosomes. However, that still leaves many gaps. Immune cells have internal regulators that are not directly tied to hormones or chromosomes, and these remain poorly studied.

One type of immune cells at the center of this problem is the T helper 2 (Th2) cell. These cells protect against parasites, however, they also drive allergic disease, such as severe asthma. Their activity has been linked to sex differences in several conditions.

The team wanted to know if factors inside Th2 cells, beyond hormones and chromosomes, might help explain these differences and whether a noncoding RNA called Malat1 – known to regulate immune responses in other T cell types – is part of this puzzle.

Malat1 only affects female immune cells, not male ones

The researchers studied T cells in animal and laboratory models. They compared mice bred without the Malat1 gene with normal mice, looking at male and female cells separately. In the lab, they grew Th2 cells and tracked how they developed. They also tested the mice in a model of lung inflammation triggered by eggs from Schistosoma mansoni, a parasite known to strongly activate Th2 cells.

In the lab studies, Malat1 loss only affected female cells. Th2 cells from females without the gene produced far fewer key signaling molecules, especially IL-10, which helps control inflammation. Under some conditions, other molecules such as IL-4 and IL-13 were also reduced.

The female cells showed other problems too. They failed to switch on their normal developmental programs, lost sensitivity to the growth signal IL-2 and instead activated a stress pathway that blocked proper development.

When the team tested the schistosome infection model, they saw the same pattern. Female mice without Malat1 had fewer IL-10–producing Th2 cells in their lungs and spleen, while males were unaffected.

“We see a drop in immune cell function in females when this gene is absent. Its loss disrupts how immune cells develop – particularly their ability to produce important molecules involved in inflammatory responses called cytokines,” said corresponding author Dr. Dimitris Lagos, a director of research at the University of York and a professor of immunology at Hull York Medical School.

Sex differences in Malat1 point to future tailored therapies

These findings suggest that immune responses are not always shared between sexes, and that treatments designed on a “one-size-fits-all” basis may fail to account for these differences.

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“Malat1 appears to be part of the bigger picture of what makes female T cells different. It is a gene that produces an RNA but not a protein. It is fascinating that even though it is present in both female and male T cells, it seems to be working differently in female cells,” said Lagos.

However, the findings are in mice, and testing in human immune cells is essential before any medical application. Malat1’s exact role in controlling gene expression is also unclear. Hormones and environmental factors may interact with Malat1 in ways not yet measured.

The team now plans to study Malat1 in human T cells and to explore how it controls interferon-related gene programs in females. The long-term goal is sex-specific therapies.

“This contributes to a rapidly developing body of knowledge that tries to explain why men and women sometimes respond differently to the same infection, allergen, inflammation trigger or immune therapy,” said Lagos.

“Understanding the biology of female immune cells could lead to more effective treatments, tailored to biological sex, for diseases of the immune system, including infections affecting millions of people in some of the poorest communities in the world and common conditions such as severe asthma,” he added.

Reference: Gwynne M, West KA, Van Dongen S, et al. Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2. J Immunol. 2025:vkaf177. doi: 10.1093/jimmun/vkaf177

This article is a rework of a press release issued by the University of York. Material has been edited for length and content.