Claudin 1–mediated positioning of DC1 to mTECs is essential for maintenance of central tolerance
Central tolerance, which relies on the presentation of self-antigens by mTECs and DCs, prevents autoimmunity by eliminating self-reactive T cells. While mTECs produce self-antigens autonomously, DCs acquire them from mTECs via cooperative antigen transfer (CAT). We previously showed that mTEC and DC subsets exhibit preferential pairing in CAT, providing a rationale for the existence of molecular determinants underpinning this pairing and its outcome. Here, we compared the transcriptomes of CAT-experienced and CAT-inexperienced DCs and identified Claudin 1 as a molecule involved in CAT and type 1 DC (DC1) maturation. DC1-specific ablation of Claudin 1 resulted in decreased CAT to late mature DC1s and dramatically diminished DC1 maturation. These phenotypes correlated with the displacement of DC1s from mTECs and their decreased expression of MHCII pathway genes. This translated into impaired Treg selection and clonal deletion, ultimately manifesting in symptoms of multiorgan autoimmunity and shortened lifespan. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance.
Authors
- Evgeny Valter
- Graham Anderson (ORCID: https://orcid.org/0000-0002-2917-4085)
- Martina Dobešová (ORCID: https://orcid.org/0000-0001-9977-2518)
- Tomáš Brabec (ORCID: https://orcid.org/0000-0002-2498-1128)
- Jan Kubovčiak (ORCID: https://orcid.org/0000-0001-6446-9797)
- Katarina Kovacova
- Adéla Čepková
- Radislav Sedláček (ORCID: https://orcid.org/0000-0002-3352-392X)
- Ondřej Ballek (ORCID: https://orcid.org/0009-0007-6950-5014)
- Petr Kašpárek (ORCID: https://orcid.org/0000-0001-6047-7538)
- Dominik Filipp (ORCID: https://orcid.org/0000-0003-2506-9330)
- Matouš Vobořil (ORCID: https://orcid.org/0000-0002-3672-7629)
- Jiří Březina (ORCID: https://orcid.org/0000-0001-6865-3874)
- Vojtěch Sýkora
- Jasper Manning (ORCID: https://orcid.org/0000-0002-2376-8288)
- Jan Dobeš (ORCID: https://orcid.org/0000-0003-1853-1603)
- Valerie Tahtahova
- David Machac
- Kristina Jancovicova
- Ondřej Štepánek
- Jan Černý
- Bernard Malissen
- Jan Pačes
- Sachiko Tsukita
- Michal Kolář
Institutions
- Charles University (CZ)
- Institute of Molecular Genetics (RU)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Centre d’Immunologie de Marseille-Luminy (FR)
- NIHR Birmingham Biomedical Research Centre (GB)
- Teikyo University (JP)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-12-11
- DOI
- https://doi.org/10.1084/jem.20250970
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00