Immune maturation has long been viewed as a developmental milestone tied to weaning, when pups are first exposed to a flood of dietary antigens and colonizing microbes. A study published in Science Bulletin now suggests this picture is incomplete: in mice, the immune competence established after weaning is not self-sustaining—it must be continuously maintained by signals from the commensal microbiota.
To address this question, Wang et al. generated a spatiotemporal single-cell transcriptomic atlas of postnatal immune development. They profiled 120,649 immune cells isolated from ten tissues of germ-free (GF) and specific pathogen-free (SPF) mice at postnatal day 16, week 4, and week 9, covering the period from just before weaning to adulthood.
Comparing the two housing conditions revealed that microbiota exposure drives coordinated, tissue- and lineage-specific remodeling of the immune system. In myeloid lineages, microbial signals promoted the acquisition and maintenance of antigen-processing capacity in monocytes, macrophages, and neutrophils, with the SPF-GF divergence progressively increasing through adulthood. In lymphocytes, commensal signals rewired metabolic and translational programs: SPF lymphocytes displayed higher oxidative phosphorylation, glycolysis, and TCA cycle activity than their GF counterparts.
Mechanistically, the study identifies PDCD4, an inhibitor of translation initiation, as a microbiota-responsive brake on lymphocyte activation. PDCD4 expression rose when microbiota was absent and restrained the effector function of CD8 + T cells; knocking down PDCD4 enhanced IFN-γ and TNF-α secretion. Importantly, this brake is dynamic rather than permanent. Co-housing GF mice with SPF mice, or transplanting fecal microbiota into antibiotic-treated mice, lowered PDCD4 and restored immune competence, whereas antibiotic depletion raised it again. Challenge with either Gram-negative bacterial LPS or Gram-positive Listeria monocytogenes reduced PDCD4 in effector CD8 + T cells, indicating that the response is not restricted to a single bacterial type. Consistently, analysis of human sepsis datasets showed that PDCD4 expression negatively correlates with T cell effector molecules, hinting at evolutionary conservation of this regulatory axis.
Together, these findings redefine postnatal immune maturation as a microbiota-dependent maintenance process rather than a one-time developmental imprint. The work provides a conceptual framework for understanding persistent immune dysfunction after microbiota disruption, and suggests that microbiota-targeted interventions could help restore immune competence.
About the institutions:
1. The Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences.
2. The School of Life Sciences at Xiamen University hosts the State Key Laboratory of Cellular Stress Biology.
Science Bulletin
Experimental study