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

Intestinal inflammation continues in a subset of celiac disease (CD) patients despite a gluten-free diet. Here, by applying multiomic single cell analysis to duodenal biopsies, we find low-grade malignancies with lymphoma driver mutations in refractory CD type 2 (RCD2) patients comprise surface CD3 negative (sCD3-) lymphocytes stalled at an innate lymphoid cell (ILC) - progenitor T cell stage undergoing extensive TCR recombination. In people with refractory CD type 1 (RCD1), who currently lack explanation, we discover sCD3+ T cells with lymphoma driver mutations forming large clones displaying inflammatory and cytotoxic molecular profiles in 6 of 10 individuals, and a single small clone in 1 of 4 active recently diagnosed CD cases. Accumulation of driver-mutated T cells and their sCD3-progenitors may explain chronic, non-responsive autoimmunity. One-Sentence Summary Treatment refractory autoimmunity in celiac disease may be explained by dysregulated T cells and progenitors that have acquired lymphoma-driver mutations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Bill and Patricia Ritchie Foundation, the Bill Ferris Scholarship, National Health and Medical Research Council Australia (NHMRC) grants APP2010084, APP2028765, APP2010134, APP1113904 and APP1176553, SPHERE Triple I and the UNSW Cellular Genomics Futures Institute. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Ethics Committees from Melbourne Health (approval n. 2020.162) and Western Sydney Health District (n. 2021/ETH01429) gave ethical approvals for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors