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

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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 sCD3- progenitors may explain chronic, non-responsive
autoimmunity.