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IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease

Nature volume 578, pages 600–604 (2020)Cite this article

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Abstract

Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.

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Fig. 1: DQ8-Dd-villin-IL-15tg mice: a gluten-dependent model of coeliac disease with villous atrophy.
Fig. 2: Cytotoxic IELs are the key effector cells that mediate tissue destruction.
Fig. 3: HLA-DQ8, CD4+ T cells and IFNγ are required for tissue destruction.
Fig. 4: DQ8-Dd-villin-IL-15tg mice represent a preclinical model for coeliac disease.

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Data availability

Source Data for Figs. 1–4 and Extended Data Figs. 1–10 are provided with the paper. The RNA sequencing experiments have been deposited into the Gene Expression Omnibus (GEO) database under the accession code GSE134900. All other data are available from the corresponding author(s) upon reasonable request.

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Acknowledgements

We thank patients with coeliac disease and their family members, as well as the University of Chicago Celiac Disease Center, for supporting our research. We thank BZ-Histo Services for the histological processing of intestinal samples. We also thank the Human Tissue Resource Center and the Integrated Light Microscopy Core Facility at the University of Chicago. This work was supported by grants from NIH: R01 DK67180 and R01 DK63158, and Digestive Diseases Research Core Center P30 DK42086 at the University of Chicago as well as by funding from F. Oliver Nicklin associated with the First Analysis Institute of Integrative Studies and the Regenstein Foundation to B.J., from the CIHR (catalyst grant in environments, genes, and chronic disease) to V.A. and L.B.B., the SickKids Foundation (NI15-040) and the Canadian Celiac Association to V.A., from NIH: R01 DK063158 and R01 DK100619 to C.K., award from the Wallonie-Bruxelles International-World Excellence and from FRQNT to T.L. The Carlino Fellowship for Celiac Disease Research from the University of Chicago Celiac Disease Center supported V.D.

Author information

Author notes

  1. These authors contributed equally: Valérie Abadie, Sangman M. Kim, Thomas Lejeune

Authors and Affiliations

  1. Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    Valérie Abadie & Thomas Lejeune

  2. Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada

    Valérie Abadie & Thomas Lejeune

  3. Department of Medicine, University of Chicago, Chicago, IL, USA

    Valérie Abadie, Sangman M. Kim, Jordan D. Ernest, Jordan Voisine, Valentina Discepolo, Cezary Ciszewski, Romain Bouziat, Kaushik Panigrahi, Matthew A. Zurenski, Ian Lawrence & Bana Jabri

  4. Committee on Immunology, University of Chicago, Chicago, IL, USA

    Sangman M. Kim, Jordan D. Ernest, Jordan Voisine, Cezary Ciszewski, Romain Bouziat & Bana Jabri

  5. Department of Biology, University of San Francisco, San Francisco, CA, USA

    Sangman M. Kim

  6. Department of Chemistry, Stanford University, Stanford, CA, USA

    Brad A. Palanski & Chaitan Khosla

  7. Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada

    Olivier Tastet, Mohamed B. F. Hawash, Anne Dumaine, Vania Yotova, Jean-Christophe Grenier & Luis B. Barreiro

  8. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    Eric V. Marietta, Irina Horwath & Joseph A. Murray

  9. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Eric V. Marietta

  10. Department of Dermatology, Mayo Clinic, Rochester, MN, USA

    Eric V. Marietta

  11. Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    Mohamed B. F. Hawash

  12. Department of Chemical Engineering, Stanford University, Stanford, CA, USA

    Chaitan Khosla

  13. Stanford ChEM-H, Stanford University, Stanford, CA, USA

    Chaitan Khosla

  14. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

    Luis B. Barreiro

  15. Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA

    Luis B. Barreiro

  16. Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA

    Bana Jabri

  17. Department of Pathology, University of Chicago, Chicago, IL, USA

    Bana Jabri

  18. University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA

    Bana Jabri

Authors
  1. Valérie Abadie
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  2. Sangman M. Kim
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Contributions

V.A. and B.J. designed the research and supervised all investigations. S.M.K., T.L., J.D.E., B.A.P., C.C., J.V., R.B., K.P., M.A.Z., A.D., V.Y. and V.A. performed experiments and analysed the data. V.D. and I.L. performed the human RNA sequencing experiments. E.V.M. and I.H. undertook serology experiments. O.T., J.-C.G., M.B.F.H. and L.B.B. performed the computational analysis. C.K., J.A.M. and L.B.B. provided intellectual input and technical support. V.A. and B.J. wrote the manuscript with the contribution of S.M.K., T.L., B.A.P. and C.K. All authors provided critical review of the manuscript.

Corresponding authors

Correspondence to Valérie Abadie or Bana Jabri.

Ethics declarations

Competing interests

B.J. and J.A.M. are consultants to Celimmune and Bionix. C.K. is a member of the Board of Directors of Protagonist Therapeutics. All other authors declare no competing interests.

Additional information

Peer review information Nature thanks Nadine Cerf-Bensussan, Arthur Kaser, Daniel Mucida and Emil Unanue for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

Extended data figures and tables

Extended Data Fig. 1 Development of villous atrophy requires IL-15 expression in both the lamina propria and epithelium.

a–g, DQ8-Dd-IL-15tg, DQ8-villin-IL-15tg and DQ8-Dd-villin-IL-15tg mice that were raised on a GFD were maintained on a GFD (sham) or fed gluten for 30 days. a, Expression of Ifng in the lamina propria was measured by qPCR (DQ8-Dd-IL-15tg sham, n = 7, gluten n = 16; DQ8-villin-IL-15tg sham, n = 13, gluten n = 12). b, Serum anti-gliadin IgG2c levels were measured by ELISA 30 days after gluten feeding (DQ8-Dd-IL-15tg sham, n = 16, gluten n = 16; DQ8-villin-IL-15tg sham, n = 15, gluten n = 15). c, Serum levels of anti-DGP IgG were measured by ELISA 30 days after gluten feeding (DQ8-Dd-IL-15tg sham, n = 10, gluten n = 10; DQ8-villin-IL-15tg sham, n = 9, gluten n = 9). d, Quantification of IELs among IECs was performed on H&E-stained ileum sections (DQ8-Dd-IL-15tg sham, n = 11, gluten n = 12; DQ8-villin-IL-15tg sham, n = 17, gluten n = 16; DQ8-Dd-villin-IL-15tg sham, n = 14, gluten n = 17). e, Left, H&E staining of paraffin-embedded ileum sections. Right, the ratio of the morphometric assessment of villus height to crypt depth (DQ8-Dd-IL-15tg sham, n = 10, gluten n = 10; DQ8-villin-IL-15tg sham, n = 17, gluten n = 19; DQ8-Dd-villin-IL-15tg sham, n = 21, gluten n = 28). f, g, Expression of Rae1 (f) and Qa-1 (g) in the intestinal epithelium was measured by qPCR. Relative expression levels in sham and gluten-fed mice for each strain are shown (DQ8-Dd-IL-15tg sham, n = 16, gluten n = 16; DQ8-villin-IL-15tg sham, n = 15, gluten n = 15; DQ8-Dd-villin-IL-15tg sham, n = 20, gluten n = 26). Data are mean ± s.e.m. (a, f, g) or mean values (b–e) from three (a–c, f, g), four (d) or six (e) independent experiments. P values were determined by one-way ANOVA with Tukey’s multiple comparison test (a–e) or unpaired, two-tailed, t-test (f, g).

Source data

Extended Data Fig. 2 Acquisition of cytotoxic properties by IELs requires IL-15 expression in both the lamina propria and epithelium.

a–j, DQ8-Dd-IL-15tg, DQ8-villin-IL-15tg and DQ8-Dd-villin-IL-15tg mice were maintained on a GFD or fed gluten for 30 days (gluten). a–i, The intestinal epithelium was isolated and analysed by flow cytometry. A subset of IELs was identified as TCRβ+CD4−CD8αβ+ cells. In parallel, IELs were identified as TCRβ+CD4−CD8+ cells by flow cytometry and quantified among IECs on H&E-stained ileum sections. a, Percentage of NKG2D+NKG2−CD8αβ+ IELs are indicated (DQ8-Dd-IL-15tg sham, n = 11, gluten n = 14; DQ8-villin-IL-15tg sham, n = 20, gluten n = 20; DQ8-Dd-villin-IL-15tg sham, n = 17, gluten n = 22). b, Numbers of NKG2D+NKG2−CD8+ IELs per 100 IECs (DQ8-Dd-IL-15tg sham, n = 11, gluten n = 13; DQ8-villin-IL-15tg sham, n = 20, gluten n = 20; DQ8-Dd-villin-IL-15tg sham, n = 16, gluten n = 19). c, Percentage of CD94+NKG2A−CD8αβ+ IELs are indicated (DQ8-Dd-IL-15tg sham, n = 10, gluten n = 10; DQ8-villin-IL-15tg sham, n = 11, gluten n = 11; DQ8-Dd-villin-IL-15tg sham, n = 9, gluten n = 10). d, Numbers of CD94+NKG2A−CD8+ IELs per 100 IECs (DQ8-Dd-IL-15tg sham, n = 10, gluten n = 10; DQ8-villin-IL-15tg sham, n = 11, gluten n = 11; DQ8-Dd-villin-IL-15tg sham, n = 9, gluten n = 10). e, Percentage of intracellular granzyme B+ IELs (DQ8-Dd-IL-15tg sham, n = 9, gluten n = 10; DQ8-villin-IL-15tg sham, n = 14, gluten n = 13; DQ8-Dd-villin-IL-15tg sham, n = 12, gluten n = 18). f, Numbers of granzyme B+ IELs per 100 IECs (DQ8-Dd-IL-15tg sham, n = 11, gluten n = 13; DQ8-villin-IL-15tg sham, n = 20, gluten n = 20; DQ8-Dd-villin-IL-15tg sham, n = 16, gluten n = 19). g, Mean fluorescent intensity (MFI) of intracellular granzyme B was measured. (DQ8-Dd-IL-15tg sham, n = 9, gluten n = 9; DQ8-villin-IL-15tg sham, n = 14, gluten n = 13; DQ8-Dd-villin-IL-15tg sham, n = 10, gluten n = 15). h, Percentage of CD8αβ+CD107a+ IELs. i, Numbers of CD8+CD107a+ IELs per 100 IECs (DQ8-Dd-IL-15tg sham, n = 7, gluten n = 6; DQ8-Dd-villin-IL-15tg sham, n = 8, gluten n = 5; DQ8-Dd-villin-IL-15tg sham, n = 5, gluten n = 4). j, Expression of Prf1 in the intestinal epithelium was measured by qPCR. Relative expression levels in sham and gluten-fed mice for each strain are shown (DQ8-Dd-IL-15tg sham, n = 16, gluten n = 16; DQ8-villin-IL-15tg sham, n = 15, gluten n = 15; DQ8-Dd-villin-IL-15tg sham, n = 20, gluten n = 26). Data are mean ± s.e.m. (j) or mean values (a–g, i) from six (a, b), three (c, d, j), five (e, f), four (g) or two (h, i) independent experiments. P values were determined by one-way ANOVA with Tukey’s multiple comparison test (a–g, i) or unpaired, two-tailed, t-test (j).

Source data

Extended Data Fig. 3 Overexpression of IL-15 in HLA-humanized DQ8 mice confers susceptibility to development of coeliac disease-like features in a gluten-dependent manner.

a–k, DQ8 and DQ8-Dd-villin-IL-15tg mice were maintained on a GFD or fed gluten for 30 days. a, Left, H&E staining of paraffin-embedded ileum sections. Scale bars, 100 µm. Right, the ratio of the morphometric assessment of villus height to crypt depth (DQ8 sham, n = 12, gluten n = 13; DQ8-Dd-villin-IL-15tg sham, n = 12, gluten n = 15). b, Villus/crypt ratio from sham-fed DQ8-Dd-villin-IL-15tg mice and DQ8-Dd-villin-IL-15tg mice fed a standard rodent chow without supplementary gluten (sham, n = 4, gluten n = 8). c, IgA (red) and CD138+ (green) plasma cells were distinguished by immunohistochemical staining of frozen ileum sections. Scale bars, 50 μm. d, Serum levels of anti-DGP IgG as measured by ELISA. Serum was collected 30 days after gluten feeding (DQ8 sham, n = 6, gluten n = 7; DQ8-Dd-villin-IL-15tg sham, n = 6, gluten n = 7). e, Quantification of IELs among IECs performed on H&E-stained ileum sections (DQ8 sham, n = 10, gluten n = 16; DQ8-Dd-villin-IL-15tg sham, n = 12, gluten n = 14). f–j, The intestinal epithelium was isolated and analysed by flow cytometry. IELs were identified as TCRβ+CD4−CD8+ and TCRβ+CD4−CD8αβ+ cells. f, Percentage of granzyme B+ IELs (DQ8 sham, n = 13, gluten n = 15; DQ8-Dd-villin-IL-15tg sham, n = 11, gluten n = 15). g, Numbers of CD8+ granzyme B+ IELs per 100 IECs (DQ8 sham, n = 11, gluten n = 14; DQ8-Dd-villin-IL-15tg sham, n = 11, gluten n = 13). h, MFI of granzyme B (DQ8 sham, n = 11, gluten n = 12; DQ8-Dd-villin-IL-15tg sham, n = 9, gluten n = 12). i, Percentage of NKG2D+NKG2− IELs (DQ8 sham, n = 13, gluten n = 17; DQ8-Dd-villin-IL-15tg sham, n = 11, gluten n = 15). j, Numbers of NKG2D+NKG2− IELs per 100 IECs (DQ8 sham, n = 12, gluten n = 16; DQ8-Dd-villin-IL-15tg sham, n = 11, gluten n = 13). k, The intestinal epithelium was isolated and analysed by flow cytometry. IECs were identified as EpCAM+CD45− cells. Percentage of Rae-1+ IECs (n = 5 mice per group). Data are mean values (a, b, d–k) from four (a, e–g, i, j), two (b, d, k) or three (c, h) independent experiments. P values were determined by one-way ANOVA with Tukey’s multiple comparison test (a, d–k) or unpaired, two-tailed, t-test (b).

Source data

Extended Data Fig. 4 A GFD decreases the anti-gluten antibody response and the number of cytotoxic IELs.

a–h, k, l, DQ8-Dd-villin-IL-15tg mice raised on a GFD were maintained on a GFD, fed gluten for 30 days, or fed gluten for 30 days and then reverted to a GFD for 30 days. a, Left, CD3ε+ T cells (red) and CD138+ plasma cells (green) were distinguished by immunohistochemistry staining of frozen ileum sections. Scale bars, 50 μm. Right, the number of CD138+ cells per section, normalized to lamina propria area (sham, n = 8 mice; gluten, n = 8 mice; gluten→GFD, n = 9 mice). b, c, Serum levels of anti-gliadin IgG (b) and anti-gliadin IgA (c) were measured by ELISA. Serum was collected sequentially in the same mice before gluten feeding (untreated), 30 days after gluten feeding (gluten d30), and 30 days after reversion to a GFD (GFD d60) (n = 12 or 13 mice per group for anti-gliadin IgG or IgA, respectively). d, Mucosal IgA deposits (red) and TG2 (green) were identified by immunohistochemistry staining of frozen ileum sections. Scale bars, 100 μm. e, Serum levels of anti-TG2 IgG antibody measured by ELISA 30 days after gluten feeding (n = 13 mice per group). f, Quantification of IELs among IECs was performed on H&E-stained ileum sections (sham, n = 8 mice; gluten, n = 12 mice; gluten→GFD, n = 9 mice). g, Left, granzyme B staining by immunohistochemistry on paraffin-embedded ileum sections. Scale bars, 20 μm. Right, number of granzyme B+ IELs per 100 IECs per mouse (sham, n = 6 mice; gluten, n = 10 mice; gluten→GFD, n = 9 mice). h, Expression of Gzmb in the intestinal epithelium was measured by qPCR. Relative expression levels in gluten and gluten→GFD groups were normalized against the expression levels observed in sham-fed DQ8-Dd-villin-IL-15tg mice (n = 6 mice per group). i, j, DQ8-Dd-villin-IL-15tg mice raised on a GFD were maintained on a GFD, fed gluten for 30 days, or fed gluten for 30 days and then reverted to a GFD for 60 or 90 days. The intestinal epithelium was isolated and analysed by flow cytometry, and IELs were identified as TCRβ+CD4−CD8αβ+ cells. Granzyme B+ IELs are indicated by percentage (i) and MFI (j) (sham, n = 6 mice; gluten, n = 8 mice; gluten→GFD, n = 8 mice). k, Expression of Prf1 in the intestinal epithelium was measured by qPCR. Analysis was performed as in h (gluten, n = 6 mice; gluten→GFD, n = 7 mice). l, The intestinal epithelium was isolated and analysed by flow cytometry. IELs were identified as TCRβ+CD4−CD8+ cells. In parallel, IELs were quantified among IECs on H&E-stained ileum sections. NKG2D+NKG2− IELs are indicated by absolute number per 100 IECs (sham, n = 8 mice; gluten, n = 11 mice; gluten→GFD, n = 9 mice). Data are mean ± s.e.m. (b, c, g–l) or mean values (a, e, f) from three (a, d, g), four (b, c, e, f) or two (h–l) independent experiments. P values were determined by one-way ANOVA with Tukey’s multiple comparison test (a–c, f, g, i, j, l) or unpaired, two-tailed, t-test (e, h, k).

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Extended Data Fig. 5 Effect of CD8+ T cell depletion on antibody production and epithelial stress markers.

a–f, Ten-week-old DQ8-Dd-villin-IL-15tg mice were treated with 200 μg anti-CD8α antibody (clone 2.43) or its isotype control (rat IgG2b) twice before and during the course of gluten feeding. a, Experimental scheme. b, c, Representative dot plots showing depletion efficiency in the blood (b) and epithelium (c) of DQ8-Dd-villin-IL-15tg mice after 30 days of anti-CD8α treatment. d, e, Expression of Rae1 (d) and Qa-1 (e) genes in the intestinal epithelium was determined by qPCR. Relative expression levels were normalized against the expression levels observed in sham-fed DQ8-Dd-villin-IL-15tg mice (gluten + isotype, n = 16; gluten + anti-CD8, n = 14). f, Serum levels of anti-DGP IgG 30 days after gluten feeding (n = 11 mice per group). Data are mean ± s.e.m. (d, e) or mean values (f) from four (b–e) or three (f) independent experiments. P values determined by unpaired, two-tailed, t-test (d–f).

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Extended Data Fig. 6 HLA-DQ8 is required for the expansion of cytotoxic IELs.

a, Cells were isolated from the mesenteric lymph nodes of DQ8-Dd-villin-IL-15tg and Dd-villin-IL-15tg mice. CD11c+CD103+ dendritic cells were analysed by flow cytometry for their expression of MHC class II and HLA-DQ8 molecules. b–f, DQ8-Dd-villin-IL-15tg and Dd-villin-IL-15tg mice raised on a GFD were maintained on a GFD or fed gluten for 30 days. b, Serum levels of anti-DGP IgG antibodies were measured by ELISA. Serum was collected 30 days after gluten feeding (DQ8-Dd-villin-IL-15tg, sham n = 17, gluten n = 28; Dd-villin-IL-15tg, sham n = 17, gluten n = 28). c, Expression of Ifng in the lamina propria was measured by qPCR. Relative expression levels in gluten groups were normalized against the expression levels observed in sham-fed DQ8-Dd-villin-IL-15tg mice and sham-fed Dd-villin-IL-15tg (DQ8-Dd-villin-IL-15tg, n = 8; Dd-villin-IL-15tg, n = 9). d–f, The intestinal epithelium was isolated and analysed by flow cytometry. IELs were identified as TCRβ+CD4−CD8+ cells. d, NKG2D+NKG2− IELs are indicated by absolute number per 100 IECs (DQ8-Dd-villin-IL-15tg, sham n = 8, gluten n = 16; Dd-villin-IL-15tg, sham n = 9, gluten n = 22). e, Granzyme B+ IELs are indicated by absolute number per 100 IECs (DQ8-Dd-villin-IL-15tg, sham n = 8, gluten n = 8; Dd-villin-IL-15tg, sham n = 9, gluten n = 10). f, MFI of intracellular granzyme B (DQ8-Dd-villin-IL-15tg, sham n = 5, gluten n = 6; Dd-villin-IL-15tg, sham n = 5, gluten n = 5). Data are mean values (b, d–f) or mean ± s.e.m. (c) from six (b, d), three (c), four (e) or two (f) independent experiments. P values were determined by ANOVA with Tukey’s multiple comparison test (b, d–f) or unpaired, two-tailed, t-test (c).

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Extended Data Fig. 7 CD4+ T cells are required for the pathogenesis of coeliac disease.

a–l, DQ8-Dd-villin-IL-15tg mice were treated with 200 or 400 μg of depleting anti-CD4 antibody (clone GK1.5) or isotype control (rat IgG2b) twice before and during the course of gluten feeding. a, Experimental scheme. b, c, Representative dot plots showing depletion efficiency in the blood (b) and mesenteric lymph nodes (MLN) (c) of DQ8-Dd-villin-IL-15tg mice. d, The intestinal epithelium was isolated and analysed by flow cytometry. IELs were identified as TCRβ+CD4−CD8+ cells. NKG2D+NKG2− IELs are indicated by absolute number per 100 IECs. (sham, n = 8; gluten + isotype, n = 20, gluten + anti-CD4, n = 12). e–h, Expression of Gzmb (e), Prf1 (f), Rae1 (g) and Qa-1 (h) in the intestinal epithelium as measured by qPCR. Relative expression levels were normalized against the expression levels observed in sham-fed DQ8-Dd-villin-IL-15tg mice (gluten + isotype, n = 12 to 17, gluten + anti-CD4, n = 8). i–l, Serum levels of anti-DGP IgG (i), anti-gliadin IgG2c (j), anti-gliadin IgG (k) and anti-gliadin IgA (l) antibodies were measured by ELISA from serum collected 30 days after gluten feeding (sham, n = 11; gluten + isotype, n = 25-26, gluten + anti-CD4, n = 11). Data are mean values (d, i–l) or mean ± s.e.m. (e–h) from four (b–l) independent experiments. P values determined by ANOVA with Tukey’s multiple comparison test (d, i–l) or unpaired, two-tailed, t-test (e–h).

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Extended Data Fig. 8 Transcriptional programs promoted by HLA-DQ8, IL-15 and gluten.

a, b, We contrasted the enrichment scores in the epithelium and the lamina propria for DQ8-Dd-villin-IL-15tg (x axis) and DQ8 (y axis) mice for all pathways enriched at an FDR < 5% in at least one of the strains. Positive or negative scores represent enrichments among genes that are more highly or lowly expressed in gluten-fed mice, respectively. The bottom right quadrant refers to pathways that in response to gluten are upregulated in DQ8-Dd-villin-IL-15tg but downregulated in DQ8 mice. c, Gene Ontology terms significantly enriched among genes differently expressed in response to gluten challenge in DQ8, Dd-villin-IL-15tg and DQ8-Dd-villin-IL-15tg mice. d, Heat map of genes showing a stronger response to gluten in DQ8-Dd-villin-IL-15tg mice as compared to DQ8 and Dd-villin-IL-15tg mice. The colours reflect the magnitude of the response to gluten (log2-transformed scale), and the stars highlight Gene Ontology terms associated with each of the genes plotted.

Extended Data Fig. 9 Effect of IFNγ and IL-21 neutralization on the development of coeliac disease.

a–i, DQ8-Dd-villin-IL-15tg mice were treated with 500 μg of anti-IFNγ (clone XMG1.2) and/or anti-IL21R (clone 4A9) antibodies or corresponding isotype controls (rat IgG1 and rat IgG2a, respectively) once before, and every 3 days during the course of gluten feeding as indicated. a, Ratio of the morphometric assessment of villus height to crypt depth (sham, n = 8, gluten + isotype, n = 7, gluten + anti-IL-21R, n = 6). b, Quantification of IELs among IECs was performed on H&E-stained ileum sections (sham, n = 8, gluten + isotype, n = 7, gluten + anti-IL-21R, n = 6). c, The intestinal epithelium was isolated and analysed by flow cytometry. IELs were identified as TCRβ+CD4−CD8+ cells. Granzyme B+ IELs are indicated by absolute number per 100 IECs (sham, n = 8, gluten + isotype, n = 7, gluten + anti-IL-21R, n = 6). d, Granzyme B+ IELs are indicated as in c (sham, n = 12, gluten + isotype, n = 16, gluten + anti-IL-21R + anti- IFNγ, n = 11). e, Quantification of IELs among IECs was performed on H&E-stained ileum sections (sham, n = 13, gluten + isotype, n = 17, gluten + anti-IL-21R+ anti-IFNγ, n = 11). f, g, Serum levels of anti-DGP IgG (f) and anti-gliadin IgG2c (g) antibodies were measured by ELISA. Serum was collected 30 days after gluten feeding (sham, n = 5 and 6, gluten + isotype, n = 8 and 7, gluten + anti-IL-21R, n = 6). h, i, Serum levels of anti-DGP IgG (h) and anti-gliadin IgG2c (i) antibodies were measured as in f and g (sham, n = 6 and 6, gluten + isotype, n = 8, gluten + anti-IFNγ, n = 6). Data are mean values (a–i) from two (a–c, f–i) or four (d, e) independent experiments. P values determined by ANOVA with Tukey’s multiple comparison test (a–i).

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Extended Data Fig. 10 Validation of DQ8-Dd-villin-IL-15tg mice as a preclinical mouse model of coeliac disease.

a, Serum anti-native gliadin peptides and anti-DGP IgG levels in gluten-fed DQ8-Dd-villin-IL-15tg mice treated with TG2 inhibitors or vehicle (gluten) were compared by ELISA (gluten n = 17; gluten + TG2 inhibitors n = 13). In all cases, serum samples were obtained on day 30 after initiating the gluten challenge. b, Similar gene regulatory mechanisms underlie the development of coeliac disease in humans and DQ8-Dd-villin-IL-15tg mice. Contrast between the Gene Ontology terms enriched among genes induced by gluten challenge in DQ8-Dd-villin-IL-15tg mice (depicted in the form of −log10(P values) on the x axis) and the Gene Ontology terms enriched among genes differently expressed between patients with coeliac disease and healthy controls (depicted in the form of −log10(P values) on the x axis) in the epithelial compartment (a) or the lamina propria (b). The transcriptional comparison was made between the intestinal epithelium and lamina propria of gluten-fed DQ8-Dd-villin-IL-15tg mice and whole duodenal biopsies of patients with active coeliac disease. Data in a are mean values from four independent experiments. P value determined by paired, two-tailed, t-test).

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Extended Data Fig. 11 Interplay between IL-15, TG2 and HLA-DQ8 promote the development of villous atrophy.

a, Representation of the respective roles of HLA-DQ8, IL-15, IFNγ, TG2, CD4+ and CD8+ T cells in promoting villous atrophy. IL-15 upregulation in the lamina propria is required to induce the adaptive anti-gluten TH1 response, and HLA-DQ8 facilitates and enhances the IFNγ response that is required for the development of villous atrophy. However, the adaptive TH1 immune response promoted by HLA-DQ8 and IL-15 in the lamina propria is insufficient to cause tissue destruction. It needs to synergize with IL-15 in the epithelium to further promote the expansion of cytolytic IELs and their degranulation, leading to CD8+ T cell-dependent killing of epithelial cells and villous atrophy. The value of this mouse model as a gluten- and HLA-DQ8-dependent pre-clinical model for coeliac disease is further emphasized by the finding that TG2 inhibition prevents villous atrophy. b, Coeliac disease can be represented as a jigsaw puzzle in which each piece representing one component of the anti-gluten immune response must interlock to lead to the development of villous atrophy—the diagnostic hallmark of active coeliac disease.

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Data Set 1: GSEA hallmark pathways.

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Data Set 2: Differentially expressed genes between sham and gluten-fed mice.

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Abadie, V., Kim, S.M., Lejeune, T. et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578, 600–604 (2020). https://doi.org/10.1038/s41586-020-2003-8

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  1. Tobias Freitag

    Concerns about the assessment of histopathology in a mouse model of
    human coeliac disease

    Abadie and colleagues [1] propose a model for human coeliac disease (CD) in which overexpression of IL-15 in the intestinal epithelium and CD4+ T cell immunity directed against gluten lead to the acquisition of an activated killer cell
    phenotype by intestinal intraepithelial CD8+ T cells, which would then mediate the destruction of intestinal villi. To test this hypothesis, the authors developed
    a mouse model based on cytokine IL-15 transgene overexpression in the intestinal epithelium and lamina propria (under both the villin [2] and the MHC class I Dd promotors [3]). They demonstrate that gluten feeding of HLA-DQ8, Dd-villin-IL-15 transgenic mice leads to the development of an adaptive T helper 1 cell-mediated immune response directed against gluten, but also the upregulation in the ileum of markers of cytotoxic intraepithelial lymphocytes, such as perforin 1, granzyme B and activating natural killer receptor NKG2D. These findings are interesting because the listed markers have been used as surrogates for intestinal damage in studies in humans and animals. Indeed, Abadie and colleagues report that ileal damage develops in the new mouse model. Further, they claim that damage in the ileum is dependent on 1) oral gluten feeding, 2) CD-associated HLA-DQ8 co-transgenic expression, and 3) tissue transglutaminase activity.

    It has previously been demonstrated that the overexpression of IL-15 in the intestinal epithelium under the non-classical MHC class I T3b promotor leads to spontaneous development of severe inflammation of the small intestine in adult mice [4]. In addition, overexpression of IL-15 under the Dd promotor, as used in the study by Abadie and colleagues, has been shown to manifest with multiorgan lymphocytic infiltration [3]. These pathological changes occurred in the absence of additional dietary or genetic manipulations. Therefore, it is questionable whether the histological changes in the ileum in the model described by Abadie and colleagues are in fact dependent on 1) gluten feeding, 2) HLA-DQ8 expression, or 3) tissue transglutaminase activity. Notably, each single one of these claims would already suggest a significant step towards the development of a truthful in vivo model of CD [5]. A gluten-sensitive model of CD has been described in Rag1-/- mice adoptively transferred with gliadin memory T cells [6], but as Abadie and colleagues point out, enteropathy in this model depends on depletion of regulatory T cells, which is not a feature of the HLA-DQ8, Dd-villin-IL-15 transgenic mouse model presented [1].

    In-depth histological analysis is vital for the development of any meaningful animal model of specific pathological conditions in humans. In human patients, CD primarily affects the proximal small intestine, and is characterized by well-documented histological changes [7]. Non-validated surrogate inflammatory biomarkers cannot replace the histological examination. Therefore, thorough investigation of at least the entire small intestine, i.e. duodenum, jejunum, and ileum, is key to the development of a rodent model of human CD.

    To substantiate their sweeping claim of a gluten-, HLA-DQ8 risk allele- and transglutaminase-dependency of histological changes in the model, Abadie and colleagues relied exclusively on the assessment of intraepithelial lymphocyte (IEL) counts and villus/crypt (V/C) ratios in the ileum. It appears that they did not assess inflammatory changes in the villus or basal lamina propria. They did not present integrative histopathological scores, as is common practice for animal experimental research in the gastroenterological field [6, 8, 9]. Furthermore, their
    choice for the assessment of the ileum, in the absence of any information provided on the proximal small intestine, i.e. the duodenum and jejunum, is not given any reasoning by the authors. This is very surprising, because the ileum is
    less frequently affected in CD than the proximal small intestine. It is also well known that the villus length decreases from duodenum to ileum in mice [10, 11]. Therefore, to choose the mouse ileum, where villi are physiologically short, as the site for the assessment of treatment/transgene-induced differences in villus length is highly questionable. In addition, V/C ratios are - as an isolated parameter - notoriously unreliable for histological assessment. This is due to various reasons, such as the effect of diets, age, and location in the intestinal compartment, as well as technical issues, e.g. sampling consistency [10], tissue orientation [12], or compression by luminal content. While these general considerations already render the basis for histological comparisons in the report by Abadie et al. questionable, it is disturbing to observe that in many of the authors’ figures of ileal cross sections the villi are compressed by feces (most clearly in Fig. 3g and 4b). Taken together, these considerations devaluate the reported villus length measurements.

    Further, since it can be challenging to distinguish the ileum from the jejunum in cross sections, mouse pathologists apply strict sampling standard operating
    procedures, and sample the ileum 1 cm proximal to the cecum [13]. No
    information on sampling is provided by Abadie and colleagues. Considering that the histology panel in Figure 1b shows three small intestinal cross sections, and there is evidence of two serosal attachments only in the middle (gluten) one, the reader could doubt that the left and right pictures show ileum at all. To specify, the terminal ileum has two serosal attachments, the mesentery and the ileocecal fold, whereas the jejunum only has the mesentery [11]. Also, villus and crypt epithelial damage is associated with changes in mitotic rate and/or cell loss through apoptosis or necrosis; this could have been checked without much effort. IEL counts may be used to quantify mucosal cell-mediated immune reactions, but they correlate poorly with villus damage in mice [14]. Finally, the
    differences in IEL counts and V/C ratios in the ileum demonstrated by Abadie
    and colleagues between experimental mice and controls are very modest (Fig. 1b, 3a,b, 4b). Given the limitations noted above, their meaning remains completely unclear.

    In addition, concerning the claim that the changes in the ileum presented in this study are dependent on HLA-DQ8 transgene expression, it is noted that Abadie et al. used HLA-DQ8 transgenic mice that were mouse MHC class II (I-Ab) competent. Therefore, it is premature to conclude that HLA-DQ8 is functional, and would lead to the recruitment of HLA-DQ8-restricted mouse CD4+ T cells in this model. The authors do not provide any evidence of CD4+ T cell HLA-DQ8 restriction. They could have demonstrated this, e.g. with the use of MHC class II-neutralizing antibodies.

    In summary, the histopathological changes in the ileum presented in the study by Abadie and colleagues are mild to moderate at best, without clear evidence of inflammation. Crucial information in particular on the duodenum and jejunum, and on dissection and ileum sampling is lacking. The study provides no reassurance that the claimed histopathological changes are caused by gluten feeding, or would depend on HLA-DQ8 transgenic expression or tissue transglutaminase, respectively. There is also no evidence that the claimed changes are not the result of transgenic overexpression of IL-15 in the intestine alone, as has previously been shown [3, 4]. Therefore, this report falls short of its central claims. To convince the reader, the study would have required an appropriate and much more thorough morphological investigation.

    Tobias L. Freitag [a], *, Leif C. Andersson [b], Anja Kipar [c, d]

    [a] Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Finland
    [b] Department of Pathology, Faculty of Medicine, University of Helsinki, Finland
    [c] Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Switzerland
    [d] Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Finland

    *corresponding author; email: tobias.freitag@helsinki.fi

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