Immune imprinting in utero

doi:10.1126/science.abl3631

GSTDTAP > 气候变化

DOI	10.1126/science.abl3631
	Immune imprinting in utero
	Mohammed Amir; Melody Y. Zeng
	2021-08-27
发表期刊	Science
出版年	2021
英文摘要	Increasing evidence suggests that immune system development begins in utero and is heavily influenced by the maternal immune status during gestation ([ 1 ][1]). Pregnancy is associated with suppression of the maternal immune system to promote the growth of the allogeneic fetus, albeit at the cost of increased susceptibility to infection ([ 2 ][2]). Mild maternal infections—such as mild urinary tract, skin, and respiratory tract infections—are often self-resolved and underdiagnosed. It remains poorly understood whether transient maternal inflammation induced by a mild infection leaves an immunologic scar in offspring. On page 982 of this issue, Lim et al. ([ 3 ][3]) tackle this question in mice and find that the cytokine interleukin-6 (IL-6), induced by a mild maternal infection, causes epigenetic imprinting of fetal intestine that has a long-term impact on immune responses to enteric pathogens and tissue inflammation in adulthood. Recent studies increasingly depict a more active and mature fetal immune landscape, implying that fetal cells are readily susceptible to maternal immune perturbations. For example, midgestation human fetal microglia (brain-resident macrophages) exhibit phagocytic and microbial sensing properties, which may confer protection against pathogens but increase the vulnerability of the fetal central nervous system to environmental perturbations ([ 4 ][4]). Likewise, human fetal mast cells can be sensitized by maternal immunoglobulin E (IgE) and increase the likelihood of developing skin and airway inflammation upon allergen encounter in newborns ([ 5 ][5]). Microbial signals during gestation are a major driver of the early development of fetal immune cells. Microbial DNAs in fetal tissues and live microbes that may activate fetal intestinal T cells and induce immune memory before birth were detected in human fetal intestines ([ 1 ][1], [ 6 ][6]). Lim et al. report tissue-specific enrichment of T helper 17 (TH17) cells in the small intestine in the adult offspring of dams (pregnant mice) that were infected transiently during midgestation with attenuated foodborne Yersinia pseudotuberculosis in the intestine. The intestinal TH17 cells in the offspring from an infected dam were reactive to commensal resident bacteria in the intestine and remained unchanged despite cross-fostering by a naïve dam, suggesting the contribution of in utero factors induced by the mild maternal infection. Lim et al. further show that the maternal infection resulted in an increase in IL-6, a cytokine that is produced mainly by macrophages during infections and promotes TH17 cell differentiation. A single injection of IL-6 in naïve dams was sufficient to induce intestinal TH17 cells in the adult offspring by increasing the numbers of accessible promoter regions of genes associated with epithelium development and TH cell differentiation in fetal intestinal epithelial cells. Intriguingly, the epigenetic alterations were not coupled with changes in gene expression in fetal intestinal epithelial cells. This suggests that additional triggers are needed to induce expression of these imprinted genes but are lacking in utero. A likely trigger could be postnatal microbial colonization of the neonatal intestine. Furthermore, Lim et al. demonstrate that prenatal injection of IL-6 in dams led to sustained epigenetic changes in adult intestinal stem cells, which originate from fetal intestinal epithelial cells ([ 7 ][7]), that favored the development of intestinal TH17 cells. This enhanced immunity against enteric Salmonella infection but also increased the severity of colitis in the offspring. Additional studies are needed to assess the predisposition to inflammatory disorders beyond the intestine because TH17 responses are associated with several autoimmune diseases, such as multiple sclerosis ([ 8 ][8]). ![Figure][9] Shaping immune development in utero Fetal immune development is sensitive to changes in the dam, including gut microbiota, diet, and inflammation, such as from vaccination. A mild, maternally restricted infection may lead to interleukin-6 (IL-6)–induced epigenetic imprinting in fetal intestinal epithelium and intestinal T helper 17 (TH17) cells in adult offspring. As a result, the adult offspring have enhanced immunity against enteric pathogens but may also be more susceptible to gut inflammation. GRAPHIC: KELLIE HOLOSKI/ SCIENCE It is still unclear why IL-6 induced by a mild maternal infection specifically targets fetal intestinal epithelial cells because other fetal cells also express the receptor, IL-6Rα. The tissue-specific imprinting by IL-6 in the fetal intestine suggests that perhaps additional signals exclusive to the fetal intestine also contribute to its heightened responsiveness to IL-6. Microbial ligands in the amniotic fluid can be swallowed by the fetus and passed through to the fetal intestine as early as midgestation ([ 9 ][10]); microbial stimulation of the fetal intestine may provide synergistic—but unidentified—signals in concert with maternal IL-6 to induce epigenetic modifications. Prenatal microbial exposure has emerged as a critical driver of immune development in early life ([ 10 ][11]–[ 12 ][12]). The fetal intestine, as a major site of microbial sensing and modulation, may be more receptive to in utero immune priming. Further investigation of factors in the fetal intestine that license this tissue with this distinct role in prenatal immune imprinting would elucidate potential therapeutic targets to mitigate harmful effects of maternal infections. Maternal immune activation (MIA), often triggered by infection, increases the risk of neurodevelopmental defects in offspring. IL-6–induced maternal TH17 cells in MIA in mice are associated with abnormal cortical changes in the fetal brain and autistic-like behaviors in offspring ([ 13 ][13]). Impairment in social behaviors, however, was not found in the offspring of IL-6–injected dams by Lim et al. The intensity and duration of the TH17 cell response as well as the specificities of TH17 cells may dictate the neurodevelopmental impact in the fetal brain. A mild maternal infection likely leads to a transient fluctuation of innate cytokines, such as IL-6, without eliciting a robust adaptive T cell response in the dam. Another intriguing aspect of the study by Lim et al. is the elucidation of tissue-specific immune imprinting in utero as a mechanism that connects immune perturbations during gestation and immune predisposition in adulthood. The immune landscape at the maternal-fetal interface can be shaped by other factors, including the maternal gut microbiota, vaccination, and dietary changes (see the figure), all of which may affect IL-6 signaling to the fetal intestine. The past few decades have seen a marked increase in the incidence of inflammatory disorders in children, including asthma, allergies, and behavioral deficits driven in part by neuroinflammation ([ 14 ][14]). Future work should address whether and how immune imprinting in utero may underlie the predisposition to inflammatory disorders. 1. [↵][15]1. A. Mishra et al ., Cell 184, 3394 (2021). [OpenUrl][16] 2. [↵][17]1. G. Mor, 2. P. Aldo, 3. A. B. Alvero , Nat. Rev. Immunol. 17, 469 (2017). [OpenUrl][18][CrossRef][19][PubMed][20] 3. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/336643
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Mohammed Amir,Melody Y. Zeng. Immune imprinting in utero[J]. Science,2021.
APA	Mohammed Amir,&Melody Y. Zeng.(2021).Immune imprinting in utero.Science.
MLA	Mohammed Amir,et al."Immune imprinting in utero".Science (2021).