Long-term programming of sex differences in immunity by prenatal exposure to stress

• Applicant: Professorin Dr. Petra Clara Arck
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Prenatal adverse environments such as the exposure to stress can impair immunity later in life of the offspring. In this context, a significant sex bias in immune disorders has been observed. Steroid hormones such as glucocorticoids are pivotal mediators of fetal development. Excess levels of glucocorticoids elicited by prenatal stress can cause cellular damage in the fetus. We previously identified differentially higher glucocorticoid levels in female compared to male offspring following prenatal stress. Moreover, hematopoietic stem cells had a differentially altered epigenetic signature in prenatally stressed females compared to stressed males. This was accompanied by a skewed frequency of lineage-committed cells, i.e. an increase of CD8+ effector T cells. Future experiments are now needed to unearth the biological consequences of prenatal stress for sex-specific immunity throughout life. We hypothesize that prenatal glucocorticoid surges in response to stress differentially affect CD8+ T cell-dependent long-term immunity in male and female offspring. In turn, sex-specific immunity against e.g. pathogens or anti-tumor responses is dampened, which perpetuates the courses of immune diseases. We will test this hypothesis by comprehensively analyzing antigen-specificity, effector functions and epigenetic stability of CD8+ T cells in male and female offspring exposed to prenatal stress. We will also evaluate the interaction of CD8+ T cells with glucocorticoids and other steroid hormones such as testosterone. The functional role of CD8+ T cell will be assessed in immune diseases with a clear female (influenza infection) or male (tumor response) sex bias. Our expected insights will advance the understanding of long-term programming of immunity, whilst promoting the identification of distinct pathways underlying the developmental origin of sex differences in immunity.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity