Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease

Mandeep Singh^{1

2}, Raymond H Y Louie^{3

4}, Jerome Samir⁴, Matthew A Field^{1

5}, Claire Milthorpe¹, Thiruni Adikari⁴, Joseph Mackie^{1

2}, Ellise Roper¹, Megan Faulks¹, Katherine J L Jackson¹, Andrew Calcino⁵, Melinda Y Hardy^{6

7}, Piers Blombery^{8

9}, Timothy G Amos¹, Ira W Deveson^{1

2}, Helen Vander Wende¹⁰, Stephen N Floor¹⁰, Scott A Read^{11

12

13}, Dmitri Shek^{11

12

13}, Antoine Guerin^{1

2}, Cindy S Ma^{1

2}, Stuart G Tangye^{1

2}, Antonio Di Sabatino^{14

15}, Marco V Lenti^{14

15}, Alessandra Pasini^{14

15}, Rachele Ciccocioppo¹⁶, Golo Ahlenstiel^{11

12

13}, Dan Suan^{1

2}, Jason A Tye-Din^{6

17}, Christopher C Goodnow^{1

18}, Fabio Luciani^{1

4}

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
² School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia.
³ School of Computer Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia.
⁴ School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
⁵ Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Smithfield, QLD 4878, Australia.
⁶ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁷ Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC 3000, Australia.
⁹ University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁰ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹¹ Westmead Institute for Medical Research, University of Sydney, Westmead, NSW 2145, Australia.
¹² Blacktown Medical School, Western Sydney University, Blacktown, NSW 2148, Australia.
¹³ Blacktown Hospital, Blacktown, NSW 2148, Australia.
¹⁴ Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia 27100, Italy.
¹⁵ First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
¹⁶ Gastroenterology Unit, Department of Medicine, University of Verona and AOUI Verona, Policlinico GB Rossi, Verona 37134, Italy.
¹⁷ Gastroenterology Department, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
¹⁸ Cellular Genomics Futures Institute and School of Biomedical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.

PMID: 40367192
DOI: 10.1126/scitranslmed.adp6812

Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease

Mandeep Singh et al. Sci Transl Med. 2025.

. 2025 May 14;17(798):eadp6812.

doi: 10.1126/scitranslmed.adp6812. Epub 2025 May 14.

Authors

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
² School of Clinical Medicine, Faculty of Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia.
³ School of Computer Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia.
⁴ School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
⁵ Australian Institute of Tropical Health and Medicine and Centre for Tropical Bioinformatics and Molecular Biology, James Cook University, Smithfield, QLD 4878, Australia.
⁶ Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁷ Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC 3000, Australia.
⁹ University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁰ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹¹ Westmead Institute for Medical Research, University of Sydney, Westmead, NSW 2145, Australia.
¹² Blacktown Medical School, Western Sydney University, Blacktown, NSW 2148, Australia.
¹³ Blacktown Hospital, Blacktown, NSW 2148, Australia.
¹⁴ Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia 27100, Italy.
¹⁵ First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
¹⁶ Gastroenterology Unit, Department of Medicine, University of Verona and AOUI Verona, Policlinico GB Rossi, Verona 37134, Italy.
¹⁷ Gastroenterology Department, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
¹⁸ Cellular Genomics Futures Institute and School of Biomedical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.

PMID: 40367192
DOI: 10.1126/scitranslmed.adp6812

Abstract

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^-) lymphocytes stalled at an innate lymphoid cell (ILC)-progenitor T cell stage undergoing extensive TRA, TRB, and TRD TCR recombination. In people with refractory celiac disease type 1 (RCD1), a disease currently lacking explanation, we identified sCD3⁺ 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^- progenitors may contribute to chronic, nonresponsive celiac disease.

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Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease

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Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease

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Abstract

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Medical