Work

Weaning imprints a hybrid cytotoxic-regulatory identity on intestinal CD4 + T lymphocytes

Year: 2026

Type: preprint

Abstract: The intestinal immune system must adapt as the neonatal gut shifts from milk to solid food and becomes densely colonized. How the T cell compartment is established under these conditions remains unclear. Using fate-mapping to timestamp naïve T cells, with imaging, transcriptomic, and repertoire analyses, we tracked them from suckling to adulthood. Intestinal T cell entry peaked at weaning, coinciding with relocation from crypts to villi guided by the tissue microenvironment and, partly, the microbiota. T cells timestamped at suckling persisted into adulthood and, at weaning, adopted a transient cytotoxic-regulatory state in the lamina propria, with granzyme B expression microbiota-dependent only in the ileum. Clonal expansions at weaning were restricted to the small intestinal lamina propria and absent in germ-free mice. Most expanded clones recognized early-life commensals. Weaning is a physiological window of transient inflammation imprinting a hybrid CD4⁺ T cell compartment, suggesting that early-life commensals modulate T cell selection.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.26.762022