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

出生前的不利环境，如暴露于压力下，会损害后代以后的免疫力。在这种情况下，在免疫疾病中观察到了显著的性别偏见。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。我们以前发现差异较高的糖皮质激素水平的女性相比，男性后代产前压力。此外，造血干细胞有差异改变的表观遗传签名在产前强调女性相比，强调男性。这伴随着谱系定型细胞的偏斜频率，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终生性特异性免疫的生物学后果。我们推测，产前糖皮质激素激增响应压力差异影响CD8+ T细胞依赖的长期免疫的男性和女性后代。反过来，针对例如病原体或抗肿瘤反应的性别特异性免疫力被抑制，这使免疫疾病的病程持续下去。我们将通过全面分析暴露于产前应激的男性和女性后代中CD8+ T细胞的抗原特异性、效应子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。将评估CD8+ T细胞在具有明显女性（流感感染）或男性（肿瘤反应）性别偏倚的免疫疾病中的功能作用。我们预期的见解将促进对免疫长期编程的理解，同时促进识别免疫性别差异发展起源的不同途径。

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.