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

Area of Science:

• Gastroenterology
• Immunology
• Oncology

Background:

• Celiac disease (CD) often persists despite a gluten-free diet (GFD) in some patients, leading to refractory celiac disease (RCD).
• Refractory celiac disease type 1 (RCD1) lacks a clear underlying mechanism, while refractory celiac disease type 2 (RCD2) is associated with specific T-cell populations.

Purpose of the Study:

• To investigate the cellular and molecular underpinnings of persistent intestinal inflammation in refractory celiac disease.
• To identify potential drivers of nonresponsive celiac disease using advanced multi-omic single-cell analysis.

Main Methods:

• Multi-omic single-cell analysis was performed on duodenal biopsies from patients with RCD1, RCD2, and active celiac disease.
• Flow cytometry and genetic sequencing were used to characterize T-cell populations and identify somatic mutations.

Main Results:

• In RCD2, surface CD3-negative (sCD3-) lymphocytes with lymphoma driver mutations were identified at an innate lymphoid cell (ILC)-progenitor T cell stage, undergoing extensive T-cell receptor (TCR) recombination.
• In RCD1, surface CD3-positive (sCD3+) T cells harboring lymphoma driver mutations were found in 60% of individuals, along with one patient with active CD.
• These mutated T cells formed large TCRαβ clones and exhibited inflammatory and cytotoxic molecular signatures.

Conclusions:

• The accumulation of lymphoma driver-mutated T cells and sCD3- progenitors may contribute to the chronic, nonresponsive nature of celiac disease.
• This study provides novel insights into the pathogenesis of refractory celiac disease, highlighting a potential role for clonal T-cell expansions.