Weaning imprints a hybrid cytotoxic-regulatory identity on intestinal CD4+ T lymphocytes
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.
Authors
- Elaine V. Fuchs (ORCID: https://orcid.org/0000-0002-0978-5137)
- Mackenzie Marie Clark
- Tiago B. R. Castro (ORCID: https://orcid.org/0000-0002-0359-0611)
- Izabela Mamede (ORCID: https://orcid.org/0000-0002-0707-5588)
- Roham Parsa (ORCID: https://orcid.org/0000-0002-0864-6098)
- Marina Schernthanner (ORCID: https://orcid.org/0000-0002-6394-6050)
- Marwa Saad (ORCID: https://orcid.org/0009-0009-4784-7747)
- Angelina Morand Bianchi Bilate (ORCID: https://orcid.org/0000-0003-4575-786X)
- Bernardo Sgarbi Reis (ORCID: https://orcid.org/0000-0002-6841-116X)
- Daniel Mucida (ORCID: https://orcid.org/0000-0002-0000-0452)
- Gabriella Lima dos Reis (ORCID: https://orcid.org/0000-0001-7511-1379)
- Alexandra Thoms (ORCID: https://orcid.org/0009-0006-4169-061X)
- Yue S. Yin
- Rohit Gokhale
Institutions
- Chan Zuckerberg Initiative (United States) (US)
- Rockefeller University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-10-27
- DOI
- https://doi.org/10.64898/2026.10.26.762022
- Primary Topic
- T-cell and B-cell Immunology
- Type
- preprint
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Gordon and Betty Moore Foundation
- Boehringer Ingelheim Fonds
- Federal Agency for Science and Innovation
- National Institutes of Health
- Kavli Institute for Theoretical Physics, University of California, Santa Barbara