Neonatal liver niches program T cell tolerance
After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1-2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4<sup>+</sup> T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions.
Authors
- Stephan P. Rosshart (ORCID: https://orcid.org/0000-0002-6989-8686)
- Natalia Torow (ORCID: https://orcid.org/0000-0003-3013-8724)
- Cristina Kalbermatter (ORCID: https://orcid.org/0009-0003-3689-291X)
- Jarrett Lopez-Scarim (ORCID: https://orcid.org/0000-0002-6941-2797)
- Solveig Runge (ORCID: https://orcid.org/0000-0002-9193-476X)
- Eva Billerbeck (ORCID: https://orcid.org/0000-0002-0477-1748)
- Vuk Cerovic (ORCID: https://orcid.org/0000-0003-1392-0669)
- Susan A. V. Jennings
- Mathias Walter Hornef (ORCID: https://orcid.org/0000-0001-6096-9110)
- Shahed Al Bounny
- Marlene Kohlhepp (ORCID: https://orcid.org/0000-0002-2828-1663)
- Adrien Guillot (ORCID: https://orcid.org/0000-0002-6002-9986)
- Eva-Lena Stange (ORCID: https://orcid.org/0000-0001-8277-0663)
- Milas Ugur (ORCID: https://orcid.org/0000-0003-2115-5389)
- J. Heckmann
- Aline Dupont (ORCID: https://orcid.org/0000-0002-5290-2810)
- Jonas Pes
- Trong-Hieu Nguyen
- Aaron Silva Sanchez
- D. Borrero Mendoza
- Stephanie C Ganal-Vonaburg
- Yunus Cetiner
- Urs Michael Moerbe
- Julian Brueck
- Christoph Kuppe
Institutions
- University of Bern (CH)
- Albert Einstein College of Medicine (US)
- Bern University of Applied Sciences (CH)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Würzburg (DE)
- University Hospital of Bern (CH)
- University of Alabama at Birmingham (US)
- Universitätsklinikum Erlangen (DE)
- Helmholtz Centre for Infection Research (DE)
- LEO Foundation (DK)
- Universitätsklinikum Würzburg (DE)
- Comprehensive Cancer Center Erlangen (DE)
- Charité - Universitätsmedizin Berlin (DE)
- RWTH Aachen University (DE)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-13
- DOI
- https://doi.org/10.64898/2026.01.13.698576
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00