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

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; Di Sabatino, A; Lenti, MV; Pasini, A; Ciccocioppo, R; Ahlenstiel, G; Suan, D; Tye-Din, JA; Goodnow, CC; Luciani, F

Author(s): 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; Di Sabatino, A; Lenti, MV; Pasini, A; Ciccocioppo, R; Ahlenstiel, G; Suan, D; Tye-Din, JA; Goodnow, CC; Luciani, F;
Details: Publication Year 2025-05-14,Volume 17,Issue #798,Page eadp6812
Journal Title: Science Translational Medicine
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.
Publisher: AAAS
Keywords: Humans; *Celiac Disease/genetics/immunology/pathology; *Mutation/genetics; *T-Lymphocytes/pathology/immunology; Clone Cells; *Lymphoma/genetics/pathology; Male; Female; Adult; Middle Aged; CD3 Complex/metabolism
Research Division(s): Immunology
PubMed ID: 40367192
Publisher's Version: https://doi.org/10.1126/scitranslmed.adp6812
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-29 02:03:25

Last Modified: 2025-05-29 02:08:05