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

Nature volume 471, pages 220–224 (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-D d -IL-15 transgenic mice fed gliadin mimic early stages of coeliac disease reflecting dysregulation in the adaptive immune response to gluten.

References

  1. Curotto de Lafaille, M. A. & Lafaille, J. J. Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30, 626–635 (2009)

    Article  CAS  Google Scholar 

  2. Faria, A. M. & Weiner, H. L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005)

    Article  CAS  Google Scholar 

  3. Jabri, B. & Sollid, L. M. Tissue-mediated control of immunopathology in coeliac disease. Nature Rev. Immunol. 9, 858–870 (2009)

    Article  CAS  Google Scholar 

  4. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007)

    Article  CAS  Google Scholar 

  5. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nature Rev. Immunol. 8, 685–698 (2008)

    Article  CAS  Google Scholar 

  6. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Mention, J. J. et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730–745 (2003)

    Article  CAS  Google Scholar 

  8. Tagaya, Y., Bamford, R. N., DeFilippis, A. P. & Waldmann, T. A. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4, 329–336 (1996)

    Article  CAS  Google Scholar 

  9. Fehniger, T. A. et al. Fatal leukemia in interleukin-15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J. Exp. Med. 193, 219–232 (2001)

    Article  CAS  Google Scholar 

  10. Caretto, D. et al. Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells. J. Immunol. 184, 30–34 (2010)

    Article  CAS  Google Scholar 

  11. Yokoyama, S. et al. Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes. Proc. Natl Acad. Sci. USA 106, 15849–15854 (2009)

    Article  ADS  CAS  Google Scholar 

  12. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)

    Article  ADS  CAS  Google Scholar 

  13. Gao, Y., Camacho, L. H. & Mehta, K. Retinoic acid-induced CD38 antigen promotes leukemia cells attachment and interferon-γ/interleukin-1β-dependent apoptosis of endothelial cells: implications in the etiology of retinoic acid syndrome. Leuk. Res. 31, 455–463 (2007)

    Article  CAS  Google Scholar 

  14. Mohty, M. et al. All-trans retinoic acid skews monocyte differentiation into interleukin-12-secreting dendritic-like cells. Br. J. Haematol. 122, 829–836 (2003)

    Article  CAS  Google Scholar 

  15. Rochette-Egly, C. & Germain, P. Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs). Nucl. Recept. Signal. 7, e005 (2009)

    Article  Google Scholar 

  16. Mazzarella, G. et al. Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis. Gastroenterology 134, 1017–1027 (2008)

    Article  CAS  Google Scholar 

  17. Nilsen, E. M. et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 37, 766–776 (1995)

    Article  CAS  Google Scholar 

  18. Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Med. 3, 797–801 (1997)

    Article  CAS  Google Scholar 

  19. Black, K. E., Murray, J. A. & David, C. S. HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J. Immunol. 169, 5595–5600 (2002)

    Article  CAS  Google Scholar 

  20. Marsh, M. N. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 102, 330–354 (1992)

    Article  CAS  Google Scholar 

  21. Meresse, B. et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366 (2004)

    Article  CAS  Google Scholar 

  22. Monteleone, I. et al. Characterization of IL-17A-producing cells in celiac disease mucosa. J. Immunol. 184, 2211–2218 (2010)

    Article  CAS  Google Scholar 

  23. Bodd, M. et al. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol. 3, 594–601 (2010)

    Article  CAS  Google Scholar 

  24. Hunt, K. A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genet. 40, 395–402 (2008)

    Article  CAS  Google Scholar 

  25. Reddy, D., Siegel, C. A., Sands, B. E. & Kane, S. Possible association between isotretinoin and inflammatory bowel disease. Am. J. Gastroenterol. 101, 1569–1573 (2006)

    Article  CAS  Google Scholar 

  26. Stephensen, C. B. & Livingston, K. A. Vitamin supplements and vaccines: maximize benefits, evaluate potential risks. Am. J. Clin. Nutr. 90, 457–458 (2009)

    Article  CAS  Google Scholar 

  27. Holmgren, J. & Czerkinsky, C. Mucosal immunity and vaccines. Nature Med. 11 (suppl.). S45–S53 (2005)

    Article  CAS  Google Scholar 

  28. Kraus, T. A. et al. Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease. Gastroenterology 126, 1771–1778 (2004)

    Article  CAS  Google Scholar 

  29. Liu, Z. et al. IL-15 is highly expressed in inflammatory bowel disease and regulates local T cell-dependent cytokine production. J. Immunol. 164, 3608–3615 (2000)

    Article  CAS  Google Scholar 

  30. Hill, J. A. et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity 29, 758–770 (2008)

    Article  CAS  Google Scholar 

  31. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)

    Article  CAS  Google Scholar 

  32. Veldhoen, M. et al. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006)

    Article  CAS  Google Scholar 

  33. Depaolo, R. W. et al. Toll-like receptor 6 drives differentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell Host Microbe 4, 350–361 (2008)

    Article  CAS  Google Scholar 

  34. Hill, J. A. et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29, 758–770 (2008)

    Article  CAS  Google Scholar 

  35. Park, S. H. et al. Selection and expansion of CD8α/α1 T cell receptor α/β1 intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules. J. Exp. Med. 190, 885–890 (1999)

    Article  CAS  Google Scholar 

  36. Lefrancois, L. & Lycke, N. Isolation of mouse small intestinal intraepithelial lymphocytes, Peyer’s patch, and lamina propria cells. Curr. Protoc. Immunol. 10.1002/0471142735.im0319s17 (2001)

  37. Bernardin, J. E., Kasarda, D. D. & Mecham, D. K. Preparation and characterization of α-gliadin. J. Biol. Chem. 242, 445–450 (1967)

    CAS  PubMed  Google Scholar 

  38. Marietta, E. et al. A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J. Clin. Invest. 114, 1090–1097 (2004)

    Article  CAS  Google Scholar 

Download references

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.).

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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

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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.

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Correspondence to B. Jabri.

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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. Nature 471, 220–224 (2011). https://doi.org/10.1038/nature09849

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