Adaptive immune responses to commensal microbes in human newborns (ADAPT-ANEW)

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.