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Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

Naturevolume 471, pages220–224 (2011)Cite this article

Abstract

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens1,2. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat3. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses4,5,6. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients3,7, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.

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Figure 1:IL-15-activated dendritic cells in the presence of retinoic acid prevent induction of Foxp3+ regulatory T cells.
Figure 2:Retinoic acid exerts an adjuvant effect on IL-15-mediated inflammatory T-cell responses.
Figure 3:Retinoic acid and IL-15 act in synergy to induce dendritic cells with proinflammatory properties in a JNK-dependent manner.
Figure 4:DQ8-Dd-IL-15 transgenic mice fed gliadin mimic early stages of coeliac disease reflecting dysregulation in the adaptive immune response to gluten.

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Acknowledgements

We thank coeliac disease patients and their family members as well as the University of Chicago Celiac Disease Center for supporting our research. We thank B. Sally, L. M. Sollid and M. Musch for critical reading of the manuscript. We thank C. Ciszewski, B. Uzunparmak, and N. Grandison for their help with the collection and analysis of human biopsies. We thank M. Constantinides for technical assistance with mice breeding. We also thank the University of Chicago flow cytometry facility for technical assistance. Dd-IL-15 transgenic mice were a gift from M. Caligiuri. RARα-deficient mice were provided by P. Chambon and C. Benoist. This work was supported by the Digestive Disease Research Core Center at the University of Chicago (DK42086), R01 DK67180 (for B.J.), R01DK71003 (for J.A.M.), and the Crohn’s and Colitis Foundation (for V.A.).

Author information

Author notes

  1. R. W. DePaolo and V. Abadie: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Chicago, Chicago, 60637, Illinois, USA

    R. W. DePaolo, V. Abadie, F. Tang, H. Fehlner-Peach, W. Wang, C. Semrad, S. S. Kupfer & B. Jabri

  2. Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    J. A. Hall & Y. Belkaid

  3. Immunology Graduate Group, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    J. A. Hall

  4. Department of Dermatology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    E. V. Marietta

  5. Department of Immunology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    E. V. Marietta

  6. US Department of Agriculture, Agricultural Research Service, Western Regional Research Center, 800 Buchanan Street, Albany, 94710, California, USA

    D. D. Kasarda

  7. Metabolism Branch, National Cancer Institute, Bethesda, 20892-1374, Maryland, USA

    T. A. Waldmann

  8. Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    J. A. Murray

  9. Department of Pediatrics, University of Chicago, Chicago, 60637, Illinois, USA

    S. Guandalini & B. Jabri

  10. Department of Pathology, University of Chicago, Chicago, 60637, Illinois, USA

    B. Jabri

Authors
  1. R. W. DePaolo

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  2. V. Abadie

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  3. F. Tang

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  4. H. Fehlner-Peach

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  8. D. D. Kasarda

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  9. T. A. Waldmann

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  10. J. A. Murray

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  11. C. Semrad

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  14. S. Guandalini

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  15. B. Jabri

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Contributions

R.W.D. and V.A. provided input into the conceptual development and execution of the studies, as well as preparation of the manuscript. F.T., H.F.-P., J.A.H. and W.W. provided technical assistance and input into data analyses. J.A.M. and E.V.M. helped with the analysis of the humanized HLA-DQ8 transgenic mice. D.D.K. provided preparations of α-gliadin used in the feeding experiments, T.A.W. provided TMβ-1 antibody, and Y.B. helped with the realization of T-cell transfer experiments and provided us with RARα-deficient bone-marrow. C.S., S.K. and S.G. followed patients with coeliac disease and provided intestinal biopsies for cytokines analysis. Y.B., J.A.M., D.D.K. and T.A.W. participated in discussion and review of the manuscript. B.J. conceived the idea, wrote the manuscript and supervised all investigations.

Corresponding author

Correspondence toB. Jabri.

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The authors declare no competing financial interests.

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DePaolo, R., Abadie, V., Tang, F.et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.Nature471, 220–224 (2011). https://doi.org/10.1038/nature09849

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Editorial Summary

Gluten intolerance mechanism

The vitamin A metabolite retinoic acid is shown to act synergistically with the cytokine interleukin-15 (IL-15) to induce IL-12p70 production by intestinal dendritic cells, thereby promoting an inflammatory T-cell response to dietary antigens. IL-15 is upregulated in the guts of patients with coeliac disease, and this new work points to a previously unknown involvement of IL-15 and retinoic acid in promoting an inflammatory immune response to gluten.

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