Sex differences in T cell metabolism

Sex is an important biological variable that affects health and disease outcomes. Nearly all diseases have some sex differences in in presentation or prevalence, for example, 80% of autoimmune disease cases are female, while biological males have almost two-fold higher risk of cancer. This manifests itself at the cellular level in higher numbers of activated CD8+ T cells, CD4+ T cells, and cytotoxic activity in females during disease. And yet typically, only male subjects have been utilized in most biomedical research.

Given the clear epidemiological and immunological differences between biological sexes, many findings may lack relevance to females. Thus, both biological sexes should be utilized more frequently, and a baseline understanding of sex differences in immunology is necessary. Metabolism is an important biological factor where sex differences have also been described at the systemic level. At the cellular level, metabolism also dictates the fate and function of immune cells but to our knowledge, cellular metabolism has not been extensively characterized in the context of sex differences. Systemic and cellular metabolism, as well as body temperature, is important for regulating T cell function, which overall influences disease outcome.

Differences in T cell activation and function between the sexes led us to propose that metabolic differences at both the cellular and systemic levels may regulate sex differences in immune responses. We compared whole-body metabolism between male and female mice, as well as T cell metabolism during homeostasis and after activation. We find that females have a higher body temperature, particularly at thermoneutrality, as well as increased b-oxidation. At the cellular level, T cells exhibit tissue dependent differences in mitochondrial metabolism between the sexes during both homeostasis and activation. Here we propose that systemic and cellular metabolic differences inherent to sex, underlies sex differences in the immune system.