A dendritic cell population responsible for transglutaminase 2–mediated gluten antigen presentation in celiac disease
Fu-Chen Yang, … , Bana Jabri, Chaitan Khosla
Fu-Chen Yang, … , Bana Jabri, Chaitan Khosla
Published August 28, 2025
Citation Information: JCI Insight. 2025;10(19):e196102. https://doi.org/10.1172/jci.insight.196102.
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Research Article Gastroenterology

A dendritic cell population responsible for transglutaminase 2–mediated gluten antigen presentation in celiac disease

Abstract

In celiac disease (CeD), a gluten-dependent autoimmune disorder, transglutaminase 2 (TG2), deamidates selected glutamine residues in gluten peptides, while HLA-DQ2 presents deamidated antigens to inflammatory T cells. The cellular sources of pathogenic TG2 and DQ2 are unclear. Using chemical biology tools, we show that intestinal CD103+ dendritic cells (DCs) couple cell-surface TG2 to the endocytic LRP1 receptor to simultaneously deamidate gluten antigens and concentrate them in lysosomes. In DQ2-transgenic mice, CD103+ DCs loaded with deamidated antigens migrate from intestinal lamina propria and Peyer’s patches into mesenteric lymph nodes, where they engage T cells. In turn, gluten antigen presentation upregulates intestinal TG2 activity. The tool (HB-230) used to establish a role of CD103+ DCs in gluten antigen presentation and TG2 activation in mice also revealed that the TG2/LRP1 pathway is active in human CD14+ monocytes. Within this population of circulating monocytes, a DC subset with the gut-homing β7-integrin marker is elevated in patients with CeD with active disease compared with nonceliac controls or patients on a gluten-free diet. Our findings not only inform the cellular basis for gluten toxicity in CeD, but they also highlight the immunologic role of an enigmatic protein of growing therapeutic relevance in CeD and other immune disorders.

Authors

Fu-Chen Yang, Harrison A. Besser, Hye Rin Chun, Megan Albertelli, Nielsen Q. Fernandez-Becker, Bana Jabri, Chaitan Khosla

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Figure 1

The TG2/LRP1 pathway allows simultaneous receptor-mediated endocytosis and deamidation of antigenic gluten peptides.

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The TG2/LRP1 pathway allows simultaneous receptor-mediated endocytosis a...
(A) Transglutaminase 2 (TG2) catalyzes deamidation of selected Gln (Q) residues in its substrates via a 2-step mechanism. In the first half-reaction, the thiol (SH) functional group of a Cys residue in the active site of TG2 forms a covalent thioester intermediate with the reactive Gln residue, resulting in the release of an ammonium (NH4+) ion. The second half-reaction involves hydrolysis of this thioester intermediate resulting in a net conversion of the Gln residue into a Glu (E) residue. Alternatively, if a suitable primary amine is available, the thioester intermediate can undergo aminolysis in the second half-reaction, leading to formation of an isopeptide bond (not shown). (B) On the surface of certain antigen-presenting cells, catalytically active TG2 (blue) captures gluten antigens (green) as their corresponding thioester intermediates (black). However, before the thioester intermediate can undergo hydrolysis, it is recognized by the low-density lipoprotein-related protein 1 (LRP1) receptor on these antigen-presenting cells. Binding to LRP1 stabilizes the transient enzyme-substrate complex while activating receptor-mediated endocytosis. The TG2-bound thioester is released and hydrolyzed in the acidic environment of endosomes, leading to endosomal delivery of the deamidated gluten peptide (red). Once in the lysosome, the deamidated gluten peptide is loaded into the antigen binding pocket of HLA-DQ2 while the TG2 protein is degraded.