Linking post-translational modification of gluten to antigen presentation: a novel pathway for antigenic gluten presentation in celiac disease 4805

Abstract Description Celiac disease (CeD) is an autoimmune-like inflammatory disorder of the small intestine triggered by dietary gluten. In CeD, the enzyme tissue transglutaminase 2 (TG2) deamidates select glutamine residues on gluten peptides, enhancing their binding to disease-associated HLA-DQ2/8 molecules on APCs. Although the biochemical importance of TG2-mediated post-translational modification of gluten is well understood, it remains unclear how a miniscule amount of deamidated gluten in the lamina propria (LP) can elicit such a rapid and strong inflammatory response in patients. Previously, we showed that TG2, in complex with α2M, gets endocytosed via the cell surface receptor LRP-1 into the endolysosomes of cells in vitro. Using HB-230, a novel probe for activated TG2, we now show that substrate-bound extracellular TG2 is actively taken up by APCs in the LP. Specifically, DCs and macrophages most efficiently internalized active TG2 and presented gluten in the context of HLA-DQ2. When TG2 was knocked out, however, their ability to uptake HB-230 and present gluten was significantly reduced. Conversely, IL-15 overexpression in the intestines enhanced HB-230 uptake, suggesting a role for IL-15 in TG2 activation—a process that remains poorly understood. Overall, our study highlights a novel pathway in which TG2 couples the post-translational modification of gluten to antigen presentation, efficiently concentrating gluten in HLA-DQ2/8 APCs to activate T cells and amplify the immune response. Funding Sources Supported by NIH R01DK063158 and UChicago Committee on Immunology T32 Topic Categories Basic Autoimmunity (BA)