Here I propose a comprehensive research program taking advantage of longitudinal blood and stool samples already collected from human newborns, that will be analysed by state-of-the art single-cell methodologies and serological assays in order to investigate the specificity, clonal structure and regulation of T and B-cell responses to commensal microbes early in life. Achieving a better understanding of such responses will enable future interventions to optimize immune-microbe interactions in all children and reduce the risk of disease. Our findings could guide novel therapeutic interventions for diseases associated with disrupted immune-microbe tolerance, such as inflammatory bowel disease, and lead to the development of improved vaccines, tailored to the unique immune systems of newborn children.