Neonatal liver niches program T cell tolerance

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract 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⁺ 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 28

1. Eva-Lena Stange Aachen Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

2. Trong-Hieu Nguyen Aachen Institute of Molecular Medicine

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Molecular Medicine, University Hospital RWTH Aachen; Aachen, Germany

3. D. Borrero Mendoza

   Albert Einstein College of Medicine

   Affiliation as printed

   Department of Medicine, Division of Hepatology, and Department of Microbiology & Immunology; Albert Einstein College of Medicine, New York, USA

4. Aiara Lobo Gomes Aachen Institute of Molecular Medicine

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Molecular Medicine, University Hospital RWTH Aachen; Aachen, Germany

5. Marlene Sophia Kohlhepp

   Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Charité-Universitätsmedizin Berlin, Department of Hepatology & Gastroenterology; Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany

6. Jonas Pes Aachen Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

7. Shahed Al Bounny Aachen Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

8. Julian Brueck Aachen Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

9. Yunus Cetiner Aachen Institute of Medical Microbiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

10. Urs Mörbe

    University of Copenhagen · LEO Foundation

    Affiliation as printed

    Department of Immunology & Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen; Copenhagen, Denmark

11. Milas Ugur

    University of Würzburg

    Affiliation as printed

    Institute of Systems Immunology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

12. Cristina Kalbermatter

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Department for Biomedical Research, University of Bern; Bern, Switzerland

    Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland

13. Jarrett Lopez-Scarim

    Albert Einstein College of Medicine

    Affiliation as printed

    Department of Medicine, Division of Hepatology, and Department of Microbiology & Immunology; Albert Einstein College of Medicine, New York, USA

14. Aline Dupont Aachen Institute of Medical Microbiology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

15. Susan A. V. Jennings Aachen Functional Microbiome Research Group Institute of Medical Microbiology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

16. Aarón Silva-Sánchez

    University of Alabama at Birmingham · UAB Medicine

    Affiliation as printed

    Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham Heersink School of Medicine; Birmingham, AL 35294, USA

17. Solveig Runge

    Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

    Affiliation as printed

    Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Erlangen Germany

    Department of Microbiome Research, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Erlangen, Germany

18. Christoph Kuppe Aachen Center for Computational Life Sciences Division of Nephrology and Clinical Immunology Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Center for Computational Life Sciences, RWTH Aachen University; Aachen, Germany

    Division of Nephrology and Clinical Immunology,Medical Faculty, RWTH Aachen University; Aachen, Germany

19. Oliver Pabst Aachen Institute of Molecular Medicine

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Molecular Medicine, University Hospital RWTH Aachen; Aachen, Germany

20. Thomas Clavel Aachen Functional Microbiome Research Group Institute of Medical Microbiology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

21. Dorothee Viemann

    Universitätsklinikum Würzburg

    Affiliation as printed

    Department of Pediatrics, University Hospital Würzburg; Würzburg, Germany

22. Stephan P. Rosshart

    Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

    Affiliation as printed

    Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Erlangen Germany

    Department of Microbiome Research, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Erlangen, Germany

23. Vuk Cerovic Aachen Institute of Molecular Medicine

    Universitätsklinikum Aachen · Helmholtz Centre for Infection Research · RWTH Aachen University

    Affiliation as printed

    Helmholtz Centre for Infection Research (HZI); Braunschweig, Germany

    Institute of Molecular Medicine, University Hospital RWTH Aachen; Aachen, Germany

24. Stephanie Christine Ganal-Vonarburg

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Department for Biomedical Research, University of Bern; Bern, Switzerland

    Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland

25. Adrien Guillot

    Universitätsklinikum Würzburg

    Affiliation as printed

    Department of Pediatrics, University Hospital Würzburg; Würzburg, Germany

26. Eva Billerbeck

    Albert Einstein College of Medicine

    Affiliation as printed

    Department of Medicine, Division of Hepatology, and Department of Microbiology & Immunology; Albert Einstein College of Medicine, New York, USA

27. Mathias Walter Hornef Aachen Institute of Medical Microbiology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany

28. Natalia Torow corresponding Aachen Institute of Medical Microbiology

    Universitätsklinikum Aachen · Helmholtz Centre for Infection Research · RWTH Aachen University

    Affiliation as printed

    Helmholtz Centre for Infection Research (HZI); Braunschweig, Germany

    Institute of Medical Microbiology, University Hospital RWTH Aachen; Aachen, Germany