The long noncoding RNA lnc13 restrains inflammatory responses to maintain oral tolerance to gluten

Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten. While HLA-DQ2/8-mediated presentation of gliadin peptides is required for disease, the mechanisms that underlie the loss of oral tolerance to gluten remain incompletely understood. Long-noncoding RNAs (lncRNAs) have been increasingly recognized as regulators of immune function, yet their role in oral tolerance has not been previously explored. Here, using a screen designed to identify lncRNAs responsive to T cell activation and enriched for CeD-associated GWAS variants, we identified lnc13 as a top candidate. In HLA-DQ8 transgenic mice lacking lnc13, unmanipulated gluten ingestion led to molecular signatures resembling human CeD and hallmark features of loss of oral tolerance to gluten: increased IFN-γ+ lymphocytes, IL-12+ myeloid cells, cytotoxic intraepithelial immune cells and crypt hyperplasia in the small intestine. Mechanistically, lnc13 binds specific DNA regulatory regions and limits immune cell responsiveness to proinflammatory signals. In particular, lnc13 restrains IL-15-driven differentiation of CD8+ natural killer-like lymphokine-activated killer cells (an IL-15-dependent pathway strongly implicated in CeD). These findings establish lnc13 as a critical noncoding modulator of oral gluten tolerance.