Sex Differences in T cell metabolism

Abstract Sex is an important biological variable as it has dramatic impacts on health and disease. Males have a greater risk for infection and severe outcomes, while females have increased incidence of autoimmunity. This is often attributed to sex differences in the immune system, as females have higher numbers of activated T cells with

more potent cytotoxic activity than males. Despite these differences, biomedical research has historically used males only and many studies still do not stratify for sex. As a result, the biology underlying sex differences in disease is poorly understood. As many discovered pathways in diseases may only be relevant to one sex, this

results in new therapeutics that are not always appropriate for both sexes. Thus, the need to understand the major driving mechanisms for sex differences in immunity is urgent. Metabolism is a major biological factor with significant sex differences. At the systemic level, there are fundamental metabolic differences between the

sexes, such as in fuel utilization, lipid metabolism in liver and adipose, and core body temperature. Cellular metabolism is heavily influenced by systemic metabolism, yet little is known about sex-specific immune cell metabolism. Cellular metabolism dictates the fate and function of immune cells as it powers all immune cell

functions but also metabolites act as signaling molecules and building blocks for effector molecules. Thus, we hypothesize that there are sex differences in immune cell metabolism, which may be related to sex differences in systemic metabolism, and these in turn influence disease outcome. Further, such

differences are likely driven by sex hormones and/or chromosomes. The specific aims to address this hypothesis are 1) to assess sex differences in T cell function and metabolism and 2) to investigate the contribution of sex hormones versus sex chromosome complement to these putative differences in the context

of viral infection. Key metabolic pathways that have sexually dimorphic expression in CD8+ and CD4+ T cells will be uncovered via imaging, untargeted metabolomics, flow cytometry and Seahorse following T cell specific or viral-induced activation in vivo. To study the mechanism behind sex-biasing factors modulating T cell

metabolism we will use the sex-reversed “four core genotype” mouse model and sex hormone receptor knockout mice. These proposed studies will provide a mechanistic basis of sex differences in T cell metabolism following activation and during viral infection. Understanding fundamental sex differences in T cell metabolism and the

sex-biasing factors that modulate them will provide a basis for future sex-specific therapeutics. My research passion for the last 5-years has been to study sex differences. Now, this F31 training plan, coupled with the research plan and the support of my Sponsor in the invigorating and collaborative research environment at

Harvard, will prepare me for my longer-term goal of an independent academic career combining the field of immunometabolism and sex differences.