Role of gut epithelial-cell derived transglutaminase 2 in the formation of celiac disease autoantibodies

Formation of autoantibodies to transglutaminase 2 (TG2) in celiac disease likely involves TG2-gluten complexes that allow gluten-specific CD4 ⁺ T cells to provide help to TG2-specific B cells. To investigate whether TG2 derived from intestinal epithelial cells (IECs) contributes to this process, we generated mice with inducible IEC-specific expression of TG2 fused to a deamidated gluten peptide (DGP) containing a T-cell epitope. Upon induction, the TG2-DGP fusion protein was expressed in IECs and released into the intestinal lumen. In HLA-DQ2.5 transgenic mice with activated gluten-specific CD4 ⁺ T cells and naive TG2-specific B cells, expression of TG2-DGP was immunogenic and drove the production of intestinal and systemic anti-TG2 autoantibodies. TG2-specific B cells predominantly expanded in Peyer’s patches, suggesting that their priming and subsequent differentiation into lamina propria TG2-specific IgA ⁺ plasma cells occurs in gut-associated lymphoid tissues. The findings demonstrate immunogenicity of IEC-derived TG2-DGP fusion antigen supporting the notion of a pathogenic role for luminal TG2 in driving anti-TG2 autoimmunity in celiac disease.