Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
Doctoral School in Systems and Molecular Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Front Immunol. 2021 Jul 30;12:674532. doi: 10.3389/fimmu.2021.674532. eCollection 2021.
Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells' profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.
早期生活逆境（ELA）与晚年发生疾病的风险密切相关，例如自身免疫性疾病、2 型糖尿病和心血管疾病。在人类中，众所周知，童年时期的早期父母分离、身体和性虐待或低社会经济地位对大脑发育、激素系统和免疫反应有重大影响。母婴分离（MD）是最接近人类情况的动物模型。这种范式会引起持久的行为效应，导致 HPA 轴的变化，并影响免疫系统。然而，ELA 后免疫反应变化的机制仍不完全清楚。在这项研究中，我们通过无偏分析 viSNE 研究了 ELA 如何改变免疫系统，并特别关注 NK 免疫细胞群体及其功能。我们已经证明，母婴分离在人类和大鼠中都显著影响成年后免疫系统的敏感性。特别是，ELA 后 NK 细胞的表型和对靶细胞系的反应明显改变。这些免疫细胞不仅对 YAC-1 细胞的细胞毒性降低，而且在 3 小时的母婴分离后成熟标志物的表达明显增加。同样，遭受 ELA 的个体的 NK 细胞的细胞毒性特征也发生显著变化，同时脱颗粒能力下降。这些结果表明，ELA 后免疫系统受损的一个关键机制可能是由于细胞衰老状态的转变，特别是 NK 细胞。阐明这种机制突出了 ELA 预防的重要性以及 NK 靶向免疫疗法如何有助于减轻 ELA 的后果。
