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

Mandeep Singh; Raymond H.Y. Louie; Jerome Samir; Matthew A. Field; Claire Milthorpe; Thiruni Adikari; Joseph Mackie; Ellise Roper; Megan Faulks; Katherine J.L. Jackson; Andrew Calcino; Melinda Y. Hardy; Piers Blombery; Timothy G. Amos; Ira W. Deveson; Helen Vander Wende; Stephen N. Floor; Scott A. Read; Dmitri Shek; Antoine Guerin; Cindy S. Ma; Stuart G. Tangye; Antonio Di Sabatino; Marco V. Lenti; Alessandra Pasini; Rachele Ciccocioppo; Golo Ahlenstiel; Dan Suan; Jason A. Tye-Din; Christopher C. Goodnow; Fabio Luciani

doi:10.1126/scitranslmed.adp6812

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

Mandeep Singh, Raymond H.Y. Louie, Jerome Samir, Matthew A. Field, Claire Milthorpe, Thiruni Adikari, Joseph Mackie, Ellise Roper, Megan Faulks, Katherine J.L. Jackson, Andrew Calcino, Melinda Y. Hardy, Piers Blombery, Timothy G. Amos, Ira W. Deveson, Helen Vander Wende, Stephen N. Floor, Scott A. Read, Dmitri Shek, Antoine GuerinCindy S. Ma, Stuart G. Tangye, Antonio Di Sabatino, Marco V. Lenti, Alessandra Pasini, Rachele Ciccocioppo, Golo Ahlenstiel, Dan Suan, Jason A. Tye-Din, Christopher C. Goodnow, Fabio Luciani

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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.

Original language	English
Article number	eadp6812
Journal	Science Translational Medicine
Volume	17
Issue number	798
DOIs	https://doi.org/10.1126/scitranslmed.adp6812
Publication status	Published - 14 May 2025

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Publisher Copyright:
Copyright © 2025 The Authors, some rights reserved.

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Singh, M., Louie, R. H. Y., Samir, J., Field, M. A., Milthorpe, C., Adikari, T., Mackie, J., Roper, E., Faulks, M., Jackson, K. J. L., Calcino, A., Hardy, M. Y., Blombery, P., Amos, T. G., Deveson, I. W., Wende, H. V., Floor, S. N., Read, S. A., Shek, D., ... Luciani, F. (2025). Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease. Science Translational Medicine, 17(798), Article eadp6812. https://doi.org/10.1126/scitranslmed.adp6812

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title = "Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease",

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.",

author = "Mandeep Singh and Louie, {Raymond H.Y.} and Jerome Samir and Field, {Matthew A.} and Claire Milthorpe and Thiruni Adikari and Joseph Mackie and Ellise Roper and Megan Faulks and Jackson, {Katherine J.L.} and Andrew Calcino and Hardy, {Melinda Y.} and Piers Blombery and Amos, {Timothy G.} and Deveson, {Ira W.} and Wende, {Helen Vander} and Floor, {Stephen N.} and Read, {Scott A.} and Dmitri Shek and Antoine Guerin and Ma, {Cindy S.} and Tangye, {Stuart G.} and Sabatino, {Antonio Di} and Lenti, {Marco V.} and Alessandra Pasini and Rachele Ciccocioppo and Golo Ahlenstiel and Dan Suan and Tye-Din, {Jason A.} and Goodnow, {Christopher C.} and Fabio Luciani",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

month = may,

day = "14",

doi = "10.1126/scitranslmed.adp6812",

language = "English",

volume = "17",

journal = "Science Translational Medicine",

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Singh, M, Louie, RHY, Samir, J, Field, MA, Milthorpe, C, Adikari, T, Mackie, J, Roper, E, Faulks, M, Jackson, KJL, Calcino, A, Hardy, MY, Blombery, P, Amos, TG, Deveson, IW, Wende, HV, Floor, SN, Read, SA, Shek, D, Guerin, A, Ma, CS, Tangye, SG, Sabatino, AD, Lenti, MV, Pasini, A, Ciccocioppo, R, Ahlenstiel, G, Suan, D, Tye-Din, JA, Goodnow, CC & Luciani, F 2025, 'Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease', Science Translational Medicine, vol. 17, no. 798, eadp6812. https://doi.org/10.1126/scitranslmed.adp6812

TY - JOUR

T1 - Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease

AU - Singh, Mandeep

AU - Louie, Raymond H.Y.

AU - Samir, Jerome

AU - Field, Matthew A.

AU - Milthorpe, Claire

AU - Adikari, Thiruni

AU - Mackie, Joseph

AU - Roper, Ellise

AU - Faulks, Megan

AU - Jackson, Katherine J.L.

AU - Calcino, Andrew

AU - Hardy, Melinda Y.

AU - Blombery, Piers

AU - Amos, Timothy G.

AU - Deveson, Ira W.

AU - Wende, Helen Vander

AU - Floor, Stephen N.

AU - Read, Scott A.

AU - Shek, Dmitri

AU - Guerin, Antoine

AU - Ma, Cindy S.

AU - Tangye, Stuart G.

AU - Sabatino, Antonio Di

AU - Lenti, Marco V.

AU - Pasini, Alessandra

AU - Ciccocioppo, Rachele

AU - Ahlenstiel, Golo

AU - Suan, Dan

AU - Tye-Din, Jason A.

AU - Goodnow, Christopher C.

AU - Luciani, Fabio

PY - 2025/5/14

Y1 - 2025/5/14

N2 - 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.

AB - 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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DO - 10.1126/scitranslmed.adp6812

M3 - Article

C2 - 40367192

AN - SCOPUS:105005472757

SN - 1946-6234

VL - 17

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 798

M1 - eadp6812

ER -

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

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