Immune–epithelial–stromal networks define the cellular ecosystem of the small intestine in celiac disease
The immune-epithelial-stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4<sup>+</sup> T cells, intraepithelial lymphocytes, CD8<sup>+</sup> and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune-epithelial 'scar'. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell-B cell interactions. Receptor-ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.
Authors
- John A. Todd (ORCID: https://orcid.org/0000-0003-2740-8148)
- Michael Fitzpatrick (ORCID: https://orcid.org/0000-0003-2365-2012)
- Lucy Howarth (ORCID: https://orcid.org/0000-0002-6963-8745)
- Darren Ruane (ORCID: https://orcid.org/0000-0002-1053-2313)
- Jane I. Pernes
- Nicholas M. Provine (ORCID: https://orcid.org/0000-0002-9694-2216)
- Agne Antanaviciute (ORCID: https://orcid.org/0000-0002-9019-2215)
- Sarah Amalia Teichmann (ORCID: https://orcid.org/0000-0002-6294-6366)
- Paul Klenerman (ORCID: https://orcid.org/0000-0003-4307-9161)
- Calliope Athena Dendrou (ORCID: https://orcid.org/0000-0003-1179-4021)
- Lucy C. Garner (ORCID: https://orcid.org/0000-0002-6461-252X)
- Sophie Irwin (ORCID: https://orcid.org/0000-0002-2821-8015)
- Melanie Dunstan (ORCID: https://orcid.org/0000-0003-3817-2142)
- Elizabeth J. Soilleux (ORCID: https://orcid.org/0000-0002-4032-7249)
- Dominik Aschenbrenner (ORCID: https://orcid.org/0000-0001-7580-2567)
- Sarah Christina Sasson (ORCID: https://orcid.org/0000-0002-5329-9072)
- Oliver Brain (ORCID: https://orcid.org/0000-0002-9091-8397)
- Dominik Trzupek
- Holm H. Uhlig (ORCID: https://orcid.org/0000-0002-6111-7355)
- Ricardo C. Ferreira (ORCID: https://orcid.org/0000-0001-5733-3285)
- Devika Agarwal (ORCID: https://orcid.org/0000-0002-5203-307X)
- Alison Simmons (ORCID: https://orcid.org/0000-0003-3454-0710)
- Jiayuan Zhang (ORCID: https://orcid.org/0000-0003-1321-0384)
- Astor Rodrigues
- Kyla Dooley
- Karolina Künnapuu (ORCID: https://orcid.org/0000-0003-1267-0194)
Institutions
- Novartis (Switzerland) (CH)
- Janssen (Belgium) (BE)
- University of California, Los Angeles (US)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- John Radcliffe Hospital (GB)
- UNSW Sydney (AU)
- University of Oxford (GB)
- Medawar Building for Pathogen Research (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- MRC Human Immunology Unit (GB)
- Oxford BioMedica (United Kingdom) (GB)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s41590-025-02146-2
- Citations
- 10
- Primary Topic
- Celiac Disease Research and Management
- Type
- article
- Field-Weighted Citation Impact
- 18.11
Funders
- Wellcome
- Academy of Medical Sciences