Weaning imprints a hybrid cytotoxic-regulatory identity on intestinal CD4+ T lymphocytes
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 naive 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.
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BibTeX
@misc{schernthanner2026weaning,
title = {{Weaning imprints a hybrid cytotoxic-regulatory identity on intestinal CD4+ T lymphocytes}},
author = {Marina Schernthanner and Rohit R. Gokhale and Alexandra Thoms and Gabriella Lima dos Reis and Marwa Saad and Mackenzie M. Clark and Yue S. Yin and Izabela Mamede and Bernardo S. Reis and Tiago B. R. Castro and Roham Parsa and Elaine Fuchs and Daniel Mucida and Angelina M. Bilate},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.762022},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.762022v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Weaning imprints a hybrid cytotoxic-regulatory identity on intestinal CD4+ T lymphocytes
AU - Marina Schernthanner
AU - Rohit R. Gokhale
AU - Alexandra Thoms
AU - Gabriella Lima dos Reis
AU - Marwa Saad
AU - Mackenzie M. Clark
AU - Yue S. Yin
AU - Izabela Mamede
AU - Bernardo S. Reis
AU - Tiago B. R. Castro
AU - Roham Parsa
AU - Elaine Fuchs
AU - Daniel Mucida
AU - Angelina M. Bilate
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.762022
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.762022v1
AB - 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 naive 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.
SN - 2692-8205
ER -