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A dendritic cell population responsible for transglutaminase 2–mediated gluten antigen presentation in celiac disease
Fu-Chen Yang, Harrison A. Besser, Hye Rin Chun, Megan Albertelli, Nielsen Q. Fernandez-Becker, Bana Jabri, Chaitan Khosla
Fu-Chen Yang, Harrison A. Besser, Hye Rin Chun, Megan Albertelli, Nielsen Q. Fernandez-Becker, Bana Jabri, Chaitan Khosla
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Research Article Gastroenterology

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

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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 3

CD103+ DCs are predominantly labeled by HB-230 in intestinal lamina propria.

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CD103+ DCs are predominantly labeled by HB-230 in intestinal lamina prop...
Mice received HB-230 at a dose of 10 mg/kg via oral administration. Two hours after administration, small intestines were collected for either snap freezing or the isolation of CD45+ cells from the lamina propria. (A) WT ileum cryosections were costained with anti-CD103 and anti-CD11c antibodies. White arrows indicate punctate HB-230–labeled cells costained with DC markers. (B) Viable CD45+ immune cells were enriched from the small intestines of HB-230–dosed WT and TG2-KO mice. DCs were gated by MHCII+CD11c+F4/80– cells, and the percentage of HB-230 among CD103+ cells with or without CD11b was analyzed based on PBS control (WT, n = 7; TG2-KO, n = 7). Small intestines from HB-230–administered WT mice were costained with various antibodies (Table 1) using the PhenoCycler multiplex staining system for immune cell characterization. (C) To verify that HB-230+CD103+ cells were DCs and not T lymphocytes, tissue sections were additionally stained with an anti-CD3 antibody. Yellow arrows show that HB-230 puncta colocalizes with CD103+CD11c+ DCs but not with CD3+CD103+ lymphocytes. (D) To verify that plasma cells did not take up HB-230 to form puncta, tissue sections were additionally stained with an anti-CD138 antibody. Yellow arrows denote HB-230 puncta colocalized with CD11c+ DCs but not with CD138+IgA+ plasma cells (indicated by white arrows). The dot plot shows the percentage of HB-230 among the cell population of each villus. P values were determined using an unpaired Mann-Whitney 2-tailed t test. **P < 0.01. Data represent mean ± SEM. A was captured under a confocal microscope at 40× magnification, and C and D were captured at 20× magnification.

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