Investigating a metabolic basis for sex differences in the immune system

There are known sex differences in the immune system, and it is typically documented that females have more potent immune responses. It is presumed that this explains, for example, why 80% of autoimmune diseases occur in females, while males have almost two-fold higher risk of cancer. As well as the immune system, there are also fundamental differences in systemic metabolism between males and females. However, most research and drug development focuses on just one sex or disregards sex in analysis and reporting. As a result, despite nearly all diseases having some sex differences in presentation or prevalence, we have only a rudimentary understanding of the mechanisms underlying these effects. Here, we investigate if fundamental sex differences in organismal metabolism are responsible for sex differences in immune cell intrinsic metabolism and function. Further, using sex reversed Sry mice, we decipher if these immunometabolic sex differences are under the control of hormones or sex chromosomes.

Firstly, we found that housing mice at thermoneutrality reveals many striking differences in both the metabolic and immune systems, that are not visible at room temperature. Chief among these were increased mitochondrial metabolism in all T cell subsets in females, which was evident at room temperate, but further enhanced at thermoneutrality. As core body temperature influences T cell metabolism and responses, as evidenced at sub-febrile and febrile temperatures, we propose that metabolic differences revealed at thermoneutrality are responsible for enhanced T cell metabolism and activation. Additionally, we found that increased body temperature in females as well as increased mitochondrial mass and mitochondrial potential in female T cells, were due to the absence of Sry, suggesting that these differences were due to hormones rather than chromosomes. Work is underway to demonstrate the effect of these immunometabolic differences in T cells in vivo, using infection and autoimmunity models.