Landscape of aberrant T cells with lymphoma driver mutations in celiac disease refractory to a gluten-free diet

In Celiac disease, both the environmental trigger (gluten) and major autoantigen (transglutaminase 2) are well characterised, but the underlying mechanisms by which rogue lymphocytes initiate and drive disease are unknown. Here, we apply multi-omic technologies that enable detailed DNA, RNA and protein measurements at the single-cell level to profile tens of thousands of immune cells isolated from small intestine duodenum biopsies from individuals with celiac disease that are refractory to a gluten free diet. We identify in multiple patients expanded T cell clones with mRNA and cell-surface protein expression profiles of cytotoxic effector cells, that harboured missense somatic mutations in T cell lymphoma driver genes STAT3, STAT5B and DDX3X. These mutations have been described as strong gain-of-function mutations in multiple T cell lymphomas, highlighting a novel mechanism by which T cell clones escape immune tolerance and adopt a rogue phenotype in refractory celiac disease.