A Systemic Wave of Neonatal Eosinophils Promotes Tissue Homeostasis and Commensalism

Abstract

The gastrointestinal (GI) tract poses a challenging site for the host immune system due to the high abundance of microbes in the gut lumen and continual exposure of foreign antigens that enter the gut through the diet. The transition from a relatively sterile environment of the womb to a world abundant with microbes requires the neonatal immune system to rapidly adapt and distinguish between harmful pathogens and harmless antigens, including beneficial commensal microbiota that colonizes the gut; laying the foundation for lifelong health, influencing susceptibility to infections, efficacy of vaccinations, and risk of developing autoimmune and allergic conditions in adulthood. Despite that the field of neonatal immunology has made significant strides in uncovering complex interactions between neonates, maternal factors, and the environment; considerable gaps remain in our understanding of specific cellular mechanisms and their developmental impacts. This study aims to bridge these gaps by exploring the functional roles of eosinophils in the neonatal GI tract and investigate their long-term effects on host health. We find that eosinophils accumulate in the GI tract postnatally, and depleting them during the first week of life impacts in the microbiota compositions and immune education, increasing vulnerability to allergic airway diseases as adults. We found that neonatal eosinophils exhibit enhanced activation and secretory activity, driven by robust FcγR3 signaling, crucial for early immune responses. Eosinophil deficiency leads to significant alterations in the intestinal immune landscape, including increased pro-inflammatory macrophages and compromised barrier integrity. This deficiency also causes microbial dysbiosis, reducing microbial diversity and affecting immune cell profiles into adulthood. Notably, neonatally depleted mice show heightened eosinophilic airway inflammation and increased susceptibility to allergic reactions following HDM challenge, underscoring the importance of early-life eosinophils in establishing immune tolerance and preventing allergic diseases. These findings highlight the essential role of neonatal eosinophils in maintaining gut homeostasis and shaping long-term immune responses. Taken together, our findings shed new light on the critical influence of neonatal eosinophils on microbiota composition and mucosal immunity. This study highlights the importance of eosinophil-mediated processes in early life and their long-lasting effects on health, emphasizing the consequences of their early-life dysregulation.