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

产前的不利环境，如暴露在压力下，会损害后代以后的免疫力。在这种情况下，已经观察到免疫疾病中存在明显的性别偏见。类固醇激素如糖皮质激素是胎儿发育的关键介质。产前压力引起的糖皮质激素水平过高会导致胎儿细胞损伤。我们之前发现，在产前压力下，雌性后代的糖皮质激素水平比雄性后代高。此外，在产前应激的女性中，与应激的男性相比，造血干细胞具有差异改变的表观遗传特征。这伴随着谱系细胞频率的扭曲，即CD8+效应T细胞的增加。现在需要进一步的实验来揭示产前压力对一生中性别特异性免疫的生物学后果。我们假设产前糖皮质激素对应激反应的激增对雄性和雌性后代CD8+ T细胞依赖性长期免疫的影响是不同的。反过来，针对病原体或抗肿瘤反应的性别特异性免疫被抑制，从而使免疫疾病的病程永久化。我们将通过综合分析暴露于产前应激的雄性和雌性后代中CD8+ T细胞的抗原特异性、效应功能和表观遗传稳定性来验证这一假设。我们还将评估CD8+ T细胞与糖皮质激素和其他类固醇激素（如睾酮）的相互作用。在明显女性（流感感染）或男性（肿瘤反应）性别偏倚的免疫性疾病中，将评估CD8+ T细胞的功能作用。我们预期的见解将促进对免疫长期规划的理解，同时促进确定免疫性别差异发育起源的不同途径。

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.