Mom’s IL-6 rewires baby’s gut immunity
Most infections that occur during pregnancy are mild and transient. However, whether such pathogen encounters can shape the long-term trajectory of the offspring’s immune system remains unclear. Lim et al. infected pregnant mice with the common food-borne pathogen Yersinia pseudotuberculosis (YopM) (see the Perspective by Amir and Zeng). Although the infection was maternally restricted and short-lived, the offspring harbored greater numbers of intestinal T helper 17 cells into adulthood. Interleukin-6 (IL-6) mediated this tissue-restricted effect by acting on the fetal intestinal epithelium during development. Although offspring from mothers infected with YopM or injected with IL-6 showed enhanced resistance to oral infection with Salmonella Typhimurium, they also exhibited higher susceptibility toward enteric inflammatory disease.
One fundamental property of the immune system is its ability to develop memory of previous encounters, resulting in enhanced responsiveness to subsequent challenges. This phenomenon includes not only the adaptive immune system but also innate cells and tissue stem cells. The concept of host imprinting by infection leading to altered responses to subsequent challenge is of particular interest in the context of pregnancy, which represents a fundamental developmental window for the immune system.
Most infections encountered by mammals, including those experienced during pregnancy, are mild and transient. How these infections shape offspring tissue immunity and tissue predisposition to inflammatory disorders in the long term remains to be addressed.
Infection of timed-pregnant dams (day 10.5) with an attenuated strain of the food-borne pathogen Yersinia pseudotuberculosis (yopM) was transient and maternally restricted. Adult offspring of previously infected dams harbored a higher number of T helper 17 (TH17) cells but no other cell subsets in the small and large intestinal lamina propria. No changes were observed at other barrier tissues. Transfer of transgenic T cells specific for a commensal antigen revealed that maternal infection affected the offspring intestinal milieu in a manner that enhanced TH17 cell reactivity toward the microbiota. Cross-fostering experiments demonstrated that the increased TH17 cells resulting from maternal infection was imprinted in utero. Among various inflammatory mediators, the cytokine interleukin-6 (IL-6) was significantly increased in the serum of dams infected with yopM. Injection of IL-6 alone to pregnant dams significantly increased TH17 cell numbers within the guts of offspring. Conversely, blockade of IL-6 in infected dams prevented this increase in offspring. Furthermore, injection of IL-6 to germ-free pregnant dams and conventionalization of their offspring after weaning revealed that prenatal establishment and postnatal maintenance of IL-6–mediated tissue imprinting are independent of the maternal microbiota but allow the offspring to mount enhanced TH17 cell responses to postnatal microbiota exposure.
IL6RA was expressed in all fetal intestinal epithelial cells, and specific deletion of IL6RA from epithelial cells significantly reduced Th17 responses within the gut of offspring from IL-6–exposed dams. Using complementary approaches, including assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and single-cell RNA sequencing, we found that increased IL-6 during pregnancy had immediate effects (on fetal cells) and long-term effects (in the adult offspring) on epithelial stem cell chromatin accessibility and downstream epithelial cell function, particularly increased expression of genes encoding for antigen presentation machinery and antimicrobial peptides.
Altered epithelial activation status suggested the possibility that this phenomenon may be associated with enhanced antimicrobial defense. To address this, we used an acute model of oral infection with Salmonella Typhimurium. Offspring from dams previously infected with yopM or injected with IL-6 during pregnancy developed enhanced resistance to Salmonella oral infection and dissemination. No differences were observed in controlling cutaneous Candida albicans infection, further supporting the idea that maternal imprinting of offspring is restricted to the gut compartment. However, enhanced exposure to IL-6 during pregnancy was associated with enhanced gut pathology in the context of naïve T cell transfer and dextran sulfate sodium–mediated colitis.
Our work proposes that a transient, mild infection encountered during prenatal development can impose lasting alterations to gut epithelial stem cells, resulting in an altered threshold of activation and enhanced resistance to gut infection. The impact of maternal infection was tissue specific and predominantly mediated by a single cytokine, IL-6, acting on epithelial stem cells during fetal development. Although this phenomenon can be coopted by the fetus to develop optimal immune fitness, altered offspring immunity imposed by maternal infection comes at the cost of enhanced susceptibility to mucosal inflammation.
The immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here, we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal interleukin-6 produced in response to infection can directly impose epigenetic changes on fetal intestinal epithelial stem cells, leading to long-lasting impacts on intestinal immune homeostasis. As a result, offspring of previously infected dams develop enhanced protective immunity to gut infection and increased inflammation in the context of colitis. Thus, maternal infection can be coopted by the fetus to promote long-term, tissue-specific fitness, a phenomenon that may come at the cost of predisposition to inflammatory disorders.