Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease
Intestinal inflammation continues in a subset of patients with celiac disease despite a gluten-free diet. Here, by applying multi-omic single-cell analysis to duodenal biopsies, we found that low-grade malignancies with lymphoma driver mutations in patients with refractory celiac disease type 2 (RCD2) are comprised by surface CD3-negative (sCD3<sup>-</sup>) lymphocytes stalled at an innate lymphoid cell (ILC)-progenitor T cell stage undergoing extensive <i>TRA</i>, <i>TRB</i>, and <i>TRD</i> TCR recombination. In people with refractory celiac disease type 1 (RCD1), a disease currently lacking explanation, we identified sCD3<sup>+</sup> T cells with lymphoma driver mutations in 6 of 10 individuals with RCD1 and in one of the patients with active, recently diagnosed celiac disease. Furthermore, the mutant T cells formed large TCRαβ clones and displayed inflammatory and cytotoxic molecular profiles. Thus, accumulation of lymphoma driver-mutated T cells and sCD3<sup>-</sup> progenitors may contribute to chronic, nonresponsive celiac disease.
Authors
- Fabio Luciani (ORCID: https://orcid.org/0000-0003-0666-6324)
- Mandeep Singh (ORCID: https://orcid.org/0000-0002-6998-3805)
- Jason A. Tye–Din (ORCID: https://orcid.org/0000-0001-7687-9654)
- Marco Vincenzo Lenti (ORCID: https://orcid.org/0000-0002-6654-4911)
- Stephen N. Floor (ORCID: https://orcid.org/0000-0002-9965-9694)
- Andrew Calcino (ORCID: https://orcid.org/0000-0002-3956-1273)
- Ellise A Roper (ORCID: https://orcid.org/0000-0003-3788-7568)
- Dan Suan (ORCID: https://orcid.org/0000-0001-5996-5120)
- Megan Faulks
- Helen Vander Wende (ORCID: https://orcid.org/0000-0002-0292-4528)
- Golo Ahlenstiel (ORCID: https://orcid.org/0000-0003-0026-1457)
- Matthew A. Field (ORCID: https://orcid.org/0000-0003-0788-6513)
- Jerome Samir (ORCID: https://orcid.org/0000-0001-6557-9373)
- Timothy G. Amos (ORCID: https://orcid.org/0000-0002-5829-6655)
- Antoine Guérin (ORCID: https://orcid.org/0000-0001-6810-1607)
- Melinda Y. Hardy (ORCID: https://orcid.org/0000-0003-4923-0678)
- S. Cindy (ORCID: https://orcid.org/0000-0001-5387-8413)
- Alessandra Pasini (ORCID: https://orcid.org/0000-0002-2768-6263)
- Joseph Mackie (ORCID: https://orcid.org/0000-0002-6571-4560)
- Rachele Ciccocioppo (ORCID: https://orcid.org/0000-0002-6297-7576)
- Katherine Jackson (ORCID: https://orcid.org/0000-0002-9952-7069)
- Christopher C. Goodnow (ORCID: https://orcid.org/0000-0001-5296-6155)
- Raymond H. Y. Louie (ORCID: https://orcid.org/0000-0002-9384-2447)
- Claire Milthorpe (ORCID: https://orcid.org/0000-0003-4836-7154)
- Stuart G. Tangye (ORCID: https://orcid.org/0000-0002-5360-5180)
- Thiruni Adikari
- Ira W. Deveson (ORCID: https://orcid.org/0000-0003-3861-0472)
- Antonio Di Sabatino (ORCID: https://orcid.org/0000-0002-0302-8645)
- Scott Read (ORCID: https://orcid.org/0000-0001-6775-2061)
- Dmitri Shek
- Piers Blombery
Institutions
- University of Verona (IT)
- The University of Sydney (AU)
- New South Wales Department of Health (AU)
- The Royal Melbourne Hospital (AU)
- Garvan Institute of Medical Research (AU)
- The University of Melbourne (AU)
- University of California, San Francisco (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Pavia (IT)
- Peter MacCallum Cancer Centre (AU)
- Australian Institute of Tropical Health and Medicine (AU)
- Blacktown & Mount Druitt Hospital (AU)
- UNSW Sydney (AU)
- Westmead Institute for Medical Research (AU)
- Policlinico San Matteo Fondazione (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- James Cook University (AU)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1126/scitranslmed.adp6812
- Citations
- 7
- Primary Topic
- Celiac Disease Research and Management
- Type
- article
- Field-Weighted Citation Impact
- 12.68