Newborns are colonised by trillions of microbes within hours of birth, and their immune systems must learn to tolerate these beneficial bacteria while still attacking dangerous pathogens. This project analyses blood samples already collected from a human birth cohort to track how T and B cells respond to colonising microbes during the first months of life. The problem is that modern practices—antibiotics, C-section delivery, and formula feeding—disrupt this ancient microbial handshake, and are linked to rising rates of allergies, asthma, and inflammatory bowel disease. Yet the fundamental mechanisms by which human newborns establish peaceful coexistence with their microbes remain unknown. This is fundamental science: the researchers will use single-cell analyses and antibody profiling to map the specificity, clonal structure, and gene regulation of commensal-reactive lymphocytes. If successful, the work will reveal how tolerance is established and how the immune system diversifies its repertoire to recognise both friendly microbes and future pathogens. That knowledge could eventually inform vaccine design, infection risk assessment, and strategies to prevent immune-mediated diseases—but the immediate goal is simply to understand a process that has shaped human health for millennia.
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Newborns are colonized by microbes at birth and during the first months of postnatal life. In order to establish symbiotic relationships with microbes, newborn immune cells must tolerate beneficial microbes, while limiting invasive pathogens (1). This ancient process, shaped by evolution, may be altered by antibiotic exposure, C-section delivery and infant formula, all of which associate with an increased risk of immune-mediated disease like allergies, asthma and inflammatory bowel disease (2). The mechanisms whereby symbiotic immune-microbe interactions are established remain poorly understood in humans. In mice, a transient immune reaction to commensals occurs after weaning, inducing regulatory T cells and tolerance which prevent immunopathology later in life (3). Whether a similar response occurs in humans early in life is not known. Interactions with commensals are also important for generating a diversified repertoire of cross-reactive lymphocytes able to recognize and respond to pathogens and vaccines. Here I propose multimodal analyses of adaptive lymphocyte responses towards colonizing microbes early in life by single-cell analyses and antibody profiling of serial blood samples already collected from a human birth cohort (6–8). By monitoring the specificity, clonal structure and transcriptional regulation of commensal-reactive T and B cells, we hope to learn how tolerance is ensured, and colonization allowed, and how commensal-specific lymphocytes are diversified, maintained and regulated to secure long-term immune-microbe mutualism. This program holds the potential for greatly expanding our knowledge of newborn immune systems and the development of healthy immune microbe interactions, with important implications for understanding immune-mediated disease, susceptibility to infections and the protective effects of vaccines.
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